CN117062918A - 抗原反应性t细胞受体 - Google Patents
抗原反应性t细胞受体 Download PDFInfo
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Abstract
本发明涉及鉴定对呈递T细胞活化抗原的细胞有反应的T细胞(癌症反应性T细胞)的方法,其包括(a)测定来自受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;(b)基于步骤(a)的测定,鉴定癌症反应性T细胞。本发明还涉及鉴定与受试者的癌细胞结合的TCR的方法,所述方法包括(A)根据上述方法鉴定癌症反应性T细胞,(B)提供步骤(A)中鉴定的癌症反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,(C)鉴定与癌细胞结合的TCR。本发明进一步涉及另外的方法和与其相关的癌症反应性T细胞。
Description
本发明涉及鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括(a)测定来自所述受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;和(b)基于步骤(a)的测定,鉴定反应性T细胞。本发明还涉及鉴定与受试者的细胞(优选癌细胞)上呈递的活化抗原结合的TCR的方法,所述方法包括(A)根据鉴定反应性T细胞的方法鉴定反应性T细胞,(B)提供步骤(a)中鉴定的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,(C)鉴定与细胞上呈递的活化抗原结合的TCR。本发明进一步涉及另外的方法和与其相关的癌症反应性T细胞。
近年来,人们对鉴定用于个性化过继细胞疗法(ACT)的抗原反应性T细胞受体(TCR)越来越感兴趣。在这种疗法中,采集患者血液中的循环T细胞,经转基因修饰以表达肿瘤反应性TCR,然后回输至患者。
作为用于鉴定例如肿瘤反应性TCR的T细胞的来源,已使用肿瘤浸润淋巴细胞(TIL)。理论上,TIL群内的肿瘤反应性T细胞可以通过其对已知T细胞活化生物标志物(例如CD69和Nur77)的上调来鉴定,尽管实际上通过这种方法鉴定的TCR的价值有限。
已经描述了T细胞活化的更多生物标志物,参见Cano-Gamez等人(2020),Nat Comm11:,art.1801(doi.org/10.1038/s41467-020-15543-y),Magen等人(2019),Cell Rep 29(10):3019(doi.org/10.1016/j.celrep.2019.10.131),和Oh等人(2020),Cell 181(7):1612(doi.org/10.1016/j.cell.2020.05.017)。此外,例如已经描述了预测对免疫检查点阻断无反应的生物标志物(WO2018/209324)和免疫治疗耐药性的生物标志物(WO2019/070755)。最近,描述了肿瘤浸润性T淋巴细胞的活化标志物(WO 2021/188954 A1,Lowery等人(2022),Science 10.1126/science.abl5447)。
在主要组织相容性复合体(MHC)的背景下,T细胞活化一直被认为涉及抗原(例如多肽的表位)的呈递。与包含CD8+ T细胞上的CD8蛋白的TCR复合体相互作用的MHC I类,由所有有核细胞表达,而与包含CD4+T细胞上的CD4蛋白的TCR复合体相互作用的MHC II类,仅由专业抗原表达呈递细胞(主要是B细胞和树突细胞)表达。然而,已发现细胞的其他表面分子也参与T细胞相互作用和活化(参见例如Iwabuchi&van Kaer(2019),Front Immunol 10:1837(doi:10.3389/fimmu.2019.01837)。
尽管如此,仍需要用于提供对特定抗原(例如癌症抗原)有反应的T细胞和相应的TCR的改进方法。该问题通过权利要求中表征并在下文中描述的实施方案来解决。
因此,本发明涉及鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定反应性T细胞。
优选地,本发明涉及鉴定对受试者的癌细胞有反应的T细胞(癌症反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定癌症反应性T细胞。
通常,本文所用的术语对于本领域普通技术人员应被赋予其普通和习惯的含义,并且除非另有说明,否则不限于特定或定制的含义。如以下所用,术语“具有”、“包含”或“包括”或其任何任意的语法变体以非排他性方式使用。因此,这些术语既可以是指除了这些术语引入的特征之外,在上下文中描述的实体中不存在另外的特征的情况,也可以是指存在一个或多个另外的特征的情况。作为实例,表述“A具有B”、“A包含B”和“A包括B”均可以指除了B之外,A中不存在其他要素的情况(即,其中A完全且排他性地由B组成的情况),以及除了B之外,实体A中还存在一个或多个另外的要素,例如要素C、要素C和D或甚至另外的要素。此外,如本领域技术人员所理解的,表述“包含一种(a和an)”优选地是指“包含一个或多个”,即等同于“包含至少一个”。因此,除非另有说明,否则涉及多项中的一项的表述优选地涉及至少一个该项,更优选地涉及其中的多个:因此,例如鉴定“一种(a)细胞”涉及鉴定至少一个细胞,优选地涉及鉴定多个细胞。
此外,如下所用,术语“优选地”、“更优选地”、“最优选地”、“特别地”、“更特别地”、“具体地”、“更具体地”或类似术语与任选的特征结合使用,不限制进一步的可能性。因此,这些术语引入的特征是任选的特征并且不旨在以任何方式限制权利要求的范围。如技术人员将认识到的,本发明可以通过使用可选的特征来进行。类似地,由“在实施方案中”、“在另外的实施方案中”或类似表述引入的特征旨在是任选的特征,对本发明的另外的实施方案没有任何限制,对本发明的范围没有任何限制,并且对以这种方式引入的特征与本发明的其他任选的或非任选的特征组合的可能性没有任何限制。
如本文所用,如果没有另外说明,术语“标准条件”是指IUPAC标准环境温度和压力(SATP)条件,即优选地,温度为25℃并且绝对压力为100kPa;还优选地,标准条件包括pH为7。此外,如果没有另外说明,术语“约”涉及相关领域中普遍接受的技术精度的指示值,优选地涉及指示值±20%、更优选±10%、最优选±5%。此外,术语“实质上”表示不存在对指示结果或使用有影响的偏差,即潜在偏差不导致指示结果偏差超过±20%、更优选±10%、最优选±5%。因此,“实质上由……组成”意指包括指定的组分,但排除除了以下之外的其他组分:作为杂质存在的材料、由于用于提供组分的工艺而存在的不可避免的材料,以及为了实现本发明的技术效果以外的目的而添加的组分。例如,使用短语“实质上由……组成”定义的组合物涵盖任何已知的可接受的添加剂、辅料、稀释剂、载体等。优选地,实质上由一组组分组成的组合物将包含小于5重量%、更优选小于3重量%、甚至更优选小于1重量%、最优选小于0.1重量%的非指定组分。
两个生物序列(优选DNA、RNA或氨基酸序列)之间的同一性程度(例如,表示为“同一性%”)可以通过本领域熟知的算法来确定。优选地,通过比较比较窗口内两个最佳比对的序列来确定同一性程度,其中与为了最佳比对而进行比较的序列相比,比较窗口中的序列片段可以包含添加或缺失(例如,空位或突出端)。通过以下计算百分比:优选地在多核苷酸或多肽的全长上,确定两个序列中出现相同残基的位置数以产生匹配位置数,将匹配位置数除以比较窗口中位置总数,并将结果乘以100,得出序列同一性百分比。可以通过Smith和Waterman(1981)的局部同源算法、通过Needleman和Wunsch(1970)的同源比对算法、通过Pearson和Lipman(1988)的相似性搜索方法、通过这些算法的计算机化实现(Wisconsin遗传学软件包,Genetics Computer Group(GCG),575Science Dr.,Madison,WI中的GAP、BESTFIT、BLAST、PASTA和TFASTA)或通过目视检查进行用于比较的序列的最佳比对。鉴于已鉴定两个序列用于比较,优选地采用GAP和BESTFIT来测定它们的最佳比对,从而确定同一性程度。优选地,使用空位权重的默认值5.00和空位权重长度的默认值0.30。在本文提及的生物序列的背景下,术语“实质上相同”表示至少80%、优选至少90%、更优选至少98%、最优选至少99%的同一性%值。如将理解的,术语实质上相同包括100%同一性。上述内容经必要修改后适用于术语“实质上互补”。
术语生物大分子(优选多核苷酸或多肽)的“片段”在本文中以广义使用,涉及包含所示序列、结构和/或功能的相应生物大分子的任何子部分,优选子结构域。因此,该术语包括通过生物大分子的实际片段化产生的子部分,而且还包括以抽象方式(例如,使用计算机)衍生自各个生物大分子的子部分。在序列信息,特别是核酸序列和/或多肽序列的背景下,术语“子序列”用于仅代表较长序列的一部分的序列。
除非本文另有具体说明,否则指定的化合物,特别是多核苷酸、多肽或其片段,例如T细胞受体(TCR)的可变区,可能包含在更大结构中,例如可以共价或非共价连接至辅助分子、载体分子、抑制剂和其他赋形剂。特别地,指定的多肽可以包含在包含另外的肽的融合多肽中,该另外的肽可以用作例如作为纯化和/或检测的标签、作为接头或用于延长化合物的体内半衰期。术语“可检测的标签”是指添加至或引入融合多肽中的氨基酸段;优选地,将标签添加至本发明的融合多肽的C-末端或N-末端。所述氨基酸段优选地实现通过特异性识别标签的抗体检测融合多肽;或它优选地实现形成功能构象,例如螯合剂;或它优选地实现可视化,例如在荧光标签的情况下。优选的可检测的标签是Myc标签、FLAG标签、6-His标签、HA标签、GST标签或荧光蛋白标签,例如GFP标签。这些标签是本领域熟知的。优选地包含在融合多肽中的其他另外的肽包含另外的氨基酸或其他修饰,其可以充当分泌介质、充当血脑屏障通过的介质、充当细胞穿透肽、和/或充当免疫刺激剂。另外的多肽或可以与该多肽融合的肽是信号和/或转运序列和/或接头序列。TCR的可变区优选地包含在如下文指定的TCRα或β链的主链中。
本文所用,术语“多肽”是指由通过肽键彼此共价连接的数个(通常至少20个)氨基酸组成的分子。由通过肽键共价连接的少于20个氨基酸组成的分子通常被认为是“肽”。优选地,多肽包含50至1000个、更优选75至750个、还更优选100至500个、最优选110至400个氨基酸。优选地,多肽包含在融合多肽和/或多肽复合体中。
优选地,本发明的鉴定反应性T细胞的方法是体外方法。除了与上文相关的步骤之外,该方法可以进一步包括另外的步骤。例如,另外的步骤可以涉及,例如,为步骤a)提供样品,或在步骤b)中测定另外的生物标志物。此外,所述步骤中的一个或多个可以由自动化设备进行或辅助。
如本文所用,术语“T细胞受体”,缩写为“TCR”,涉及T细胞表面上的多肽复合体,其介导由靶细胞呈递的抗原肽的识别,优选地在MHC分子或MHC相关分子(例如MR1或CD1)的背景下,更优选地在MHC分子的背景下,还更优选地在MHC I类或MHC II类分子的背景下,最优选地在MHC I类分子的背景下。通常,TCR包含一条TCR-α链和一条TCR-β链,即是α/β链异二聚体。然而,TCR还可以包含TCRγ和TCRδ链而不是TCRα和β链。TCRα和β链或γ和δ链介导抗原识别并且各自包含跨膜区、恒定区、连接区和可变区,每个TCRα、β、γ或δ链的可变区包含三个互补决定区(CDR),分别称为CDR1、CDR2和CDR3。根据通常的命名法,在本文中由α和β链或γ和δ链组成的复合体被称为“T细胞受体”或“TCR”,α和/或β链以及γ和/或δ链共同或单独地被称为“一种TCR多肽”或“多种TCR多肽”,而包含TCR和辅助多肽(例如CD3和CD247)的多肽复合体被称为“T细胞受体复合体”,缩写为“TCR复合体”。优选地,T细胞受体结合主要组织相容性复合体(MHC)分子,优选MHC I类或II类,更优选MHC I类分子,其呈递促成疾病和/或与疾病相关的抗原,优选癌症抗原或自身免疫T细胞抗原,更优选癌症抗原,还更优选癌症特异性抗原的表位,特别是癌细胞的新表位。T细胞受体与抗原的结合可以通过技术人员已知的方法测定,例如通过本文实施例中指定的方法,或例如在四聚体测定中。优选地,TCR与MHC上呈递的表位的结合活化T细胞。各种类型T细胞的活化生物标志物是本领域已知的并且特别包括CD69、CD137、CD27、TRAP/CD40L和CD134。TCR还可以是可溶性TCR。原则上,术语“可溶性TCR”是本领域技术人员已知的,涉及如上文指定的缺乏跨膜结构域的TCR。因此,优选地,可溶性TCR包含TCR的TCR多肽的恒定区和可变区。更优选地,可溶性TCR包含TCR的TCR多肽的可变区,优选地以融合多肽的形式。
术语“互补决定区”,缩写为“CDR”,是本领域技术人员所理解的。如本领域已知的,每个TCRα、β、γ和δ链包含三个CDR,它们是提供决定TCR与如本文其他地方指定的MHC分子呈递的肽的接触的表位特异性的肽。
术语“T细胞”被技术人员理解为涉及表达至少一种类型的如上文指定的T细胞受体的淋巴细胞。优选地,T细胞是识别靶细胞表面上MHC I类分子的CD8+ T细胞,或是识别靶细胞表面上MHC II类分子的CD4+ T细胞,更优选地是CD8+ T细胞。优选地,T细胞是细胞毒性T细胞,更优选CD8+细胞毒性T细胞,其也可以被称为“杀伤细胞”。还优选地,T细胞是调节性T细胞或辅助性T细胞,更优选调节性T细胞。优选地,T细胞是α/βT细胞,即表达包含TCRα和TCRβ链的T细胞受体的T细胞。优选地,T细胞对呈递T细胞活化抗原的细胞有反应,即“反应性T细胞”,更优选地对呈递T细胞活化抗原的细胞有特异性反应;因此,优选地T细胞由呈递T细胞活化抗原的细胞活化,优选地由呈递T细胞活化抗原的细胞特异性活化,术语“由呈递T细胞活化抗原的细胞特异性活化”和“对呈递T细胞活化抗原的细胞有特异性反应”表明该T细胞优选地由呈递T细胞活化抗原的细胞活化,但不由不呈递T细胞活化抗原的细胞活化,特别是同一组织的。可以通过本领域已知的方法,例如通过测量细胞因子分泌,例如干扰素-γ分泌,或通过本文实施例中指定的方法测量T细胞的活化。优选地,T细胞对癌细胞有反应,即是“癌症反应性T细胞”,或对呈递T细胞自身抗原的细胞有反应,即是“自身免疫反应性T细胞”。因此,优选地,T细胞表达识别癌症抗原、优选癌特异性抗原的TCR,如以下所指定的。根据上文,对癌细胞有反应的T细胞是表达识别癌症抗原、优选癌特异性抗原的TCR的T细胞。还优选地,T细胞表达识别自身免疫T细胞抗原、优选特异性自身免疫T细胞抗原的TCR。
术语“T细胞活化抗原”,还可使用表述“活化抗原”,在本文中以广义使用,其涉及受试者细胞表面上存在的任何结构,其可以活化表达适当TCR的T细胞。优选地,抗原是多肽或其片段、多糖或脂质。更优选地,在MHC分子的背景下,抗原是由所述受试者的所述细胞呈递的多肽的表位,优选地如上文所指定的。如技术人员理解的,如果通过本文指定的方法在样品中鉴定反应性T细胞,优选地假设所述受试者中存在呈递T细胞活化抗原的细胞;由于该鉴定不一定包括鉴定T细胞活化抗原,所以所鉴定的反应性T细胞和/或其TCR可以进一步用于鉴定T细胞活化抗原。优选地,T细胞活化抗原是癌症抗原或自身免疫相关T细胞活化抗原。因此,反应性T细胞可以特别是癌症反应性T细胞或自身免疫反应性T细胞。
如本文所用,术语“癌症”涉及动物(包括人)的疾病,其特征在于一组体细胞(“癌细胞”)不受控制的生长。这种不受控制的生长可能伴有周围组织的侵入和破坏,并且癌细胞可能扩散至身体的其他部位。优选地,术语癌症还包括复发。因此,优选地,癌症是实体癌、其转移或其复发。癌症可以由感染原,优选病毒,更优选致癌病毒,更优选EB病毒、肝炎病毒、人T嗜淋巴细胞病毒1、乳头瘤病毒或人疱疹病毒8诱导。然而,癌症还可能由化合物(例如致癌物)诱发,或例如由自发突变内源性引起。
优选地,癌症选自由以下组成的列表:急性淋巴细胞白血病、急性髓细胞白血病、肾上腺皮质癌、艾滋病相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎瘤、基底细胞癌、胆管癌、膀胱癌、脑干胶质瘤、乳腺癌、伯基特淋巴瘤、类癌、小脑星形细胞瘤、宫颈癌、脊索瘤、慢性淋巴细胞白血病、慢性粒细胞白血病、结肠癌、结直肠癌、颅咽管瘤、子宫内膜癌、室管膜母细胞瘤、室管膜瘤、食道癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、肝外胆管癌、纤维肉瘤、胆囊癌、胃癌、胃肠道间质瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、肝细胞癌、霍奇金淋巴瘤、下咽癌、下丘脑和视觉通路胶质瘤、眼内黑色素瘤、卡波西肉瘤、喉癌、髓母细胞瘤、髓上皮瘤、黑色素瘤、梅克尔细胞癌、间皮瘤、口腔癌、多发性内分泌肿瘤综合征、多发性骨髓瘤、蕈样肉瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔癌、口咽癌、骨肉瘤、卵巢癌、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低度恶性潜能肿瘤、胰腺癌、乳头状瘤病、鼻窦及鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、垂体瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、赛塞利综合征、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状颈癌、睾丸癌、喉癌、胸腺癌、胸腺瘤、甲状腺癌、尿道癌、子宫癌、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症和维尔姆斯瘤。更优选地,癌症是实体癌、其转移或其复发。更优选地,所述癌症是胶质母细胞瘤、胰腺导管腺癌、骨肉瘤或非脑原发性肿瘤的脑转移瘤。
术语“癌症抗原”涉及由癌细胞表达的抗原,优选多肽。优选地,癌症抗原在非癌细胞中以低至少5倍、优选至少10倍、更优选至少25倍的速率表达。优选地,癌症抗原在受试者的相同组织的非肿瘤细胞中不表达,更优选地在受试者的非癌细胞中不表达;因此,癌症抗原优选是癌症特异性抗原。更优选地,癌症抗原是新抗原和/或包含由癌细胞表达的新表位。优选地,癌症抗原的一种或多种肽通过MHC分子呈递,更优选地,在产生所述癌症抗原作为“癌表位”的宿主细胞表面上的MHC I类分子,优选地,其是癌症特异性表位或如上所述的癌症新表位。如本文其他地方所指定的,癌症优选是实体癌,即形成肿瘤的癌症;因此,癌症抗原优选是肿瘤抗原,更优选肿瘤特异性抗原,并且癌表位优选是肿瘤表位,更优选肿瘤特异性表位。
原则上,技术人员已知术语“自身免疫T细胞活化抗原”涉及由受试者的细胞呈递的任何抗原,其识别引起、加重或促成自身免疫疾病,优选T细胞介导的自身免疫性疾病。T细胞介导的自身免疫性疾病是本领域已知的;优选地,T细胞介导的自身免疫性疾病选自由多发性硬化症、乳糜泻、类风湿性关节炎、1型糖尿病、甲状腺功能减退症和艾迪生病组成的列表。如技术人员理解的,本文提出的自身免疫反应性T细胞和/或其TCR的鉴定优选特别适用于诊断、有助于诊断和/或预测T细胞介导的自身免疫性疾病。然而,自身免疫反应性T细胞和/或其TCR还可用于产生调节性T细胞,因此可用于治疗T细胞介导的自身免疫性疾病。此外,自身免疫反应性T细胞和/或其TCR优选用于鉴定新的自身免疫T细胞活化抗原。
如本文所用,术语“宿主细胞”涉及能够表达并且优选地在其表面上呈递如本文所指定的TCR多肽的任何细胞,该TCR多肽优选地由多核苷酸和/或载体编码。优选地,细胞是细菌细胞,更优选地是本领域已知的常见实验室细菌菌株的细胞,最优选地是埃希氏菌属菌株,特别是大肠杆菌菌株。还优选地,宿主细胞是真核细胞,优选酵母细胞,例如面包酵母菌株的细胞,或是动物细胞。更优选地,宿主细胞是昆虫细胞或哺乳动物细胞,特别是小鼠或大鼠细胞。最优选地,宿主细胞是人细胞。优选地,宿主细胞是T细胞,更优选CD8+ T细胞或CD4+ T细胞,更优选CD8+ T细胞。如技术人员理解的,CD4 TCR优选在CD8+ T细胞中表达,并且CD4 TCR优选在CD8 T细胞中表达。
如本文所用,术语“鉴定对呈递T细胞活化抗原的细胞有反应的T细胞”和“鉴定反应性T细胞”以广义使用,包括提供关于反应性T细胞的信息以实现确定其TCR的至少CDR序列的任何和所有方式和方法。因此,反应性T细胞不必但可以以物理形式提供。因此,鉴定反应性T细胞可以包括鉴定指示表达至少一种如本文其他地方指定的生物标志物的T细胞的数据集,并且,任选地,至少分配所述反应性T细胞的TCR的CDR序列。优选地,所述数据集是或曾经是通过基因表达的单细胞测定、优选通过单细胞RNA测序来测定的。因此,鉴定反应性T细胞的方法的步骤a)可以包括对样品中T细胞的基因表达进行单细胞测定,其中测定至少一种指定的生物标志物的表达,从而鉴定反应性T细胞;任选地,至少对发现表达所述至少一种生物标志物的所述T细胞的TCR的CDR序列进行测序。然而,鉴定反应性T细胞还可以包括物理地提供所述反应性T细胞。因此,鉴定反应性T细胞的方法的步骤a)可以包括测定T细胞上和/或T细胞中指定的至少一种生物标志物的表达。因此,表面生物标志物的表达可以例如通过抗体染色,任选地随后进行FACS测量和/或分选来测定。还优选地,单个T细胞呈克隆生长并测定所述克隆生长的细胞的等分试样中的生物标志物表达。测定T细胞、优选活T细胞中生物标志物表达的其他方法是本领域已知的。
生物标志物表达的测定可以基于技术人员认为合适的任何生物标志物基因产物的量来进行。因此,测定可以包括测定RNA,特别是mRNA和/或多肽基因产物的量。然而,表达还可以通过测量替代生物标志物(例如报告基因构建体,其中报告基因在相应生物标志物的启动子的控制下表达)的表达来确定。优选地,表达的测定包括测定mRNA和/或多肽基因产物的量。
鉴定反应性T细胞包括测定如本文其他地方指定的至少一种生物标志物的表达。生物标志物的表达可以定性、半定量或定量测定,这些术语原则上是技术人员已知的。定性测定可以是T细胞表达或不表达生物标志物的二元评估,例如通过测定生物标志物的表达是否高于测定的检测水平。半定量测定可以包括将表达分类成表达类别,例如低表达、中表达或高表达。术语“定量测定”被技术人员理解为包括提供关于细胞中生物标志物的量的信息的每次或每个测定以及通过至少一种标准数学运算(特别包括浓度的计算,平均值、中位值或平均数的计算,归一化和类似计算)从该量导出的所有值。
优选地,鉴定反应性T细胞包括将T细胞中测定的生物标志物表达与参照进行比较。如本文所用,术语“参照”是指参照细胞中生物标志物的表达,例如参照细胞中生物标志物的量。优选地,参照是基因产物的阈值(例如,量或量的比率)。然而,参照还可以是通过本领域技术人员认为合适的任何数学方法(特别是归一化)从量导出的值。根据前述方法,参照优选是从已知为反应性T细胞的T细胞样品获得的参照。在这种情况下,在样品中发现的生物标志物基因产物的值与所述参照实质上相同,表明存在反应性T细胞。还优选地,参照来自已知不具有反应性的T细胞样品。在这种情况下,T细胞中发现的生物标志物基因产物的值相对于参照增加表明T细胞具有反应性。对于未刺激的T细胞群的生物标志物基因产物的相对值或绝对值,这同样适用于计算的参照值,最优选平均值或中位值。如技术人员所理解的,任何给定的天然T细胞群中每次仅有一小部分T细胞将具有反应性。相应地,上述对已知未活化的T细胞群的描述可以在经必要的修改后应用于活化状态未知的天然T细胞群;因此,参照可以是反应状态未知的T细胞天然样品。在这种情况下,T细胞中发现的生物标志物基因产物的值相对于参照增加表明T细胞具有反应性。如何计算合适的参照值,优选平均值或中位值,是本领域熟知的。之前提及的未刺激的T细胞群应包含多个T细胞,优选至少10个、更优选至少100个、还更优选至少1,000个、最优选至少10,000个未刺激的T细胞。如果相应值实质上相同,则目标T细胞的生物标志物基因产物的值和参照值实质上相同。实质上相同意指两个值之间的差异优选地不显著,并且其特征应在于这些值至少在参照值的第1和99个百分位数、第5和95个百分位数、第10和90个百分位数、第20和80个百分位数、第30和70个百分位数、第40和60个百分位数之间的区间内,优选地,参照值的第50、60、70、80、90或95个百分位数。用于确定两个量是否实质上相同的统计学检验是本领域熟知的。在另一方面,观察到的两个值的差异应当优选地具有统计学显著性。优选地,相对值或绝对值的差异在参照值的第45和55个百分位数、第40和60个百分位数、第30和70个百分位数、第20和80个百分位数、第10和90个百分位数、第5个和95个百分位数、第1和99个百分位数之间的区间之外是显著的。优选地,参照被存储在合适的数据存储介质中,例如数据库,并且因此还可用于将来的评估。
鉴定反应性T细胞包括测定CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中至少一种的表达,优选CCL4、CCL4L2、CCL3和CCL3L1中至少一种的表达。因此,鉴定反应性T细胞的方法优选地包括测定选自由CCL4、CCL4L2、CCL3、CCL3L1和CXCL13组成的列表的至少一种生物标志物的表达。因此,鉴定反应性T细胞的方法优选地包括测定选自本文中下表1的至少一种生物标志物的表达。上述生物标志物是“核心特征”的生物标志物,即每种生物标志物单独或其任何组合指示反应性T细胞。上述生物标志物原则上是本领域技术人员已知的,并且它们的氨基酸序列和编码多核苷酸序列可从公共数据库获得。“CCL4”也称为“趋化因子(C-C基序)配体4”,并且人CCL4的氨基酸序列可从例如Genbank登录号NP_996890.1获得。“CCL4L2”也称为“C-C基序趋化因子4-样2”,并且人CCL4L2的氨基酸序列可从例如Genbank登录号NP_001278397.1获得。“CCL3”也称为“趋化因子(C-C基序)配体3”,并且也可称为巨噬细胞炎症蛋白1-α(MIP-1-α);人CCL3的氨基酸序列可从例如Genbank登录号NP_002974.1获得。“CCL3L1”也称为趋化因子(C-C基序)配体3-样1”,并且人CCL3L1的氨基酸序列可从例如Genbank登录号NP_066286.1获得。“CXCL13”也被称为“B淋巴细胞化学吸引剂”和“B细胞吸引趋化因子1”,并且人CXCL13的氨基酸序列可从例如Genbank登录号NP_006410.1获得。优选地,CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达指示反应性T细胞。更优选地,至少两种、更优选至少三种、最优选全部四种前述生物标志物的表达指示反应性T细胞。
因此,在优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含以下,优选地由以下组成:CCL3L1;CCL3L1+CCL4;CCL3L1+CCL4L2;CCL3L1+CCL3;CCL3L1+CXCL13;CCL3L1+CCL4+CCL4L2;CCL3L1+CCL4+CCL3;CCL3L1+CCL4+CXCL13;CCL3L1+CCL4L2+CCL3;CCL3L1+CCL4L2+CXCL13;CCL3L1+CCL3+CXCL13;CCL3L1+CCL4+CCL4L2+CCL3;CCL3L1+CCL4+CCL4L2+CXCL13;CCL3L1+CCL4+CCL3+CXCL13;CCL3L1+CCL4L2+CCL3+CXCL13;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13;CCL4;CCL4+CCL4L2;CCL4+CCL3;CCL4+CXCL13;CCL4+CCL4L2+CCL3;CCL4+CCL4L2+CXCL13;CCL4+CCL3+CXCL13;CCL4+CCL4L2+CCL3+CXCL13;CCL4L2;CCL4L2+CCL3;CCL4L2+CXCL13;CCL4L2+CCL3+CXCL13;CCL3;CCL3+CXCL13;或CXCL13。
优选地,本文提及的鉴定反应性T细胞的方法进一步包括测定选自由以下组成的列表的至少一种生物标志物的表达:IFNG、HAVCR2、FNBP1、CSRNP1、SPRY1、RHOH、FOXN2、HIF1A、TOB1、RILPL2、CD8B、GABARAPL1、TNFSF14、EGR1、EGR2、TAGAP、TNFSF9、ANXA1、MAP3K8、PIK3R1、DUSP2、DUSP4、DUSP6、CLIC3、RASGEF1B、LAG3、XCL2、NR4A2、DNAJB6、NFKBID、MCL1、EVI2A、SLC7A5、H3F3B、NR4A3、REL、IRF4、CST7、ATF3、TNF、GPR171、BCL2A1、ITGA1、TNFAIP3、NR4A1、RUNX3、HERPUD2、FASLG、CBLB、PTGER4、SLA、XCL1、BHLHE40、LYST、KLRD1、ZNF682、CTSW、SLC2A3、NLRP3、SCML4、VSIR、LINC01871和ZFP36L1。因此,鉴定反应性T细胞的方法优选地包括测定选自本文中下表2的至少一种生物标志物的表达。生物标志物是“辅助1特征”的生物标志物,即表2的每种生物标志物单独或与表2的至少一种另外的生物标志物组合,如果与表1的至少一种生物标志物组合测定,则指示反应性T细胞。因此,优选地,除了CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种之外,表2的至少一种生物标志物的表达指示反应性T细胞。
优选地,鉴定本文提及的反应性T细胞的方法进一步包括测定选自由CCL5、GZMH、CLEC2B、GZMA、CD69、GZMK和CRTAM组成的列表的至少一种生物标志物的表达。因此,鉴定反应性T细胞的方法优选地包括测定选自本文中下表3的至少一种生物标志物的表达。生物标志物是“辅助2特征”的生物标志物,即表3的每种生物标志物单独或与表2或表3的至少一种另外的生物标志物组合,如果与表1的至少一种生物标志物组合测定,则指示反应性T细胞。因此,优选地,除了CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种之外,表3的至少一种生物标志物的表达指示反应性T细胞。
鉴于以上所述,表1至3的所有生物标志物当在T细胞中表达时,指示反应性T细胞和/或可有助于鉴定反应性T细胞。优选地,该方法进一步包括测定至少一种排除生物标志物,即当表达时指示T细胞不具有反应性的生物标志物:优选地,鉴定本文提及的反应性T细胞的方法进一步包括测定选自由GNLY和FGFBP2(表4)组成的列表中的至少一种生物标志物的表达,其中所述生物标志物中的至少一种的表达指示非反应性T细胞。因此,生物标志物GNLY和/或FGFBP2可以用作排除生物标志物。在优选的实施方案中,FOXP3可以用作(另外的)排除生物标志物。
在优选的实施方案中,鉴定反应性T细胞包括测定CCL3L1、LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B中的至少一种的表达。因此,鉴定反应性T细胞的方法优选地包括测定选自由CCL3L1、LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B组成的列表的至少一种生物标志物的表达。因此,鉴定反应性T细胞的方法优选地包括测定选自本文中下表5的至少一种生物标志物的表达。上述生物标志物是“核心-2特征”的生物标志物,即每个生物标志物单独或其任何组合指示反应性T细胞,并且在本文中也可以统称为“7个可选核心基因”。上述生物标志物原则上是本领域技术人员已知的,并且它们的氨基酸序列和编码多核苷酸序列可从公共数据库获得。CCL3L1如上文所述。“LAG3”也称为淋巴细胞活化3,并且人LAG3的氨基酸序列可从例如Genbank登录号NP_002277.4获得。“GABARAPL1”也称为GABA A型受体相关蛋白样1,并且人GABARAPL1的氨基酸序列可从例如Genbank登录号NP_001350527.1获得。“CBLB”也称为Cbl原癌基因B,并且人CBLB的氨基酸序列可从例如Genbank登录号NP_001308715.1获得。“SLA”也称为Src样衔接头,并且人SLA的氨基酸序列可从例如Genbank登录号NP_001039021.1获得。“KLRD1”也被称为杀伤细胞凝集素样受体D1,并且人KLRD1的氨基酸序列可从例如Genbank登录号NP_001107868.2获得。“CLEC2B”也称为C型凝集素结构域家族2成员B,并且人CLEC2B的氨基酸序列可从例如Genbank登录号NP_005118.2获得。优选地,CCL3L1、LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B中的至少一种的表达指示反应性T细胞。更优选地,至少两种、更优选至少三种、甚至更优选至少四种、甚至更优选至少五种、还更优选至少六种、最优选全部七种前述生物标志物的表达指示反应性T细胞。
因此,在优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含以下,优选地由以下组成:CCL3L1;CCL3L1+LAG3;CCL3L1+GABARAPL1;CCL3L1+CBLB;CCL3L1+SLA;CCL3L1+KLRD1;CCL3L1+CLEC2B;CCL3L1+LAG3+GABARAPL1;CCL3L1+LAG3+CBLB;CCL3L1+LAG3+SLA;CCL3L1+LAG3+KLRD1;CCL3L1+LAG3+CLEC2B;CCL3L1+GABARAPL1+CBLB;CCL3L1+GABARAPL1+SLA;CCL3L1+GABARAPL1+KLRD1;CCL3L1+GABARAPL1+CLEC2B;CCL3L1+CBLB+SLA;CCL3L1+CBLB+KLRD1;CCL3L1+CBLB+CLEC2B;CCL3L1+SLA+KLRD1;CCL3L1+SLA+CLEC2B;CCL3L1+KLRD1+CLEC2B;CCL3L1+LAG3+GABARAPL1+CBLB;CCL3L1+LAG3+GABARAPL1+SLA;CCL3L1+LAG3+GABARAPL1+KLRD1;CCL3L1+LAG3+GABARAPL1+CLEC2B;CCL3L1+LAG3+CBLB+SLA;CCL3L1+LAG3+CBLB+KLRD1;CCL3L1+LAG3+CBLB+CLEC2B;CCL3L1+LAG3+SLA+KLRD1;CCL3L1+LAG3+SLA+CLEC2B;CCL3L1+LAG3+KLRD1+CLEC2B;CCL3L1+GABARAPL1+CBLB+SLA;CCL3L1+GABARAPL1+CBLB+KLRD1;CCL3L1+GABARAPL1+CBLB+CLEC2B;CCL3L1+GABARAPL1+SLA+KLRD1;CCL3L1+GABARAPL1+SLA+CLEC2B;CCL3L1+GABARAPL1+KLRD1+CLEC2B;CCL3L1+CBLB+SLA+KLRD1;CCL3L1+CBLB+SLA+CLEC2B;CCL3L1+CBLB+KLRD1+CLEC2B;CCL3L1+SLA+KLRD1+CLEC2B;CCL3L1+LAG3+GABARAPL1+CBLB+SLA;CCL3L1+LAG3+GABARAPL1+CBLB+KLRD1;CCL3L1+LAG3+GABARAPL1+CBLB+CLEC2B;CCL3L1+LAG3+GABARAPL1+SLA+KLRD1;CCL3L1+LAG3+GABARAPL1+SLA+CLEC2B;CCL3L1+LAG3+GABARAPL1+KLRD1+CLEC2B;CCL3L1+LAG3+CBLB+SLA+KLRD1;CCL3L1+LAG3+CBLB+SLA+CLEC2B;CCL3L1+LAG3+CBLB+KLRD1+CLEC2B;CCL3L1+LAG3+SLA+KLRD1+CLEC2B;CCL3L1+GABARAPL1+CBLB+SLA+KLRD1;CCL3L1+GABARAPL1+CBLB+SLA+CLEC2B;CCL3L1+GABARAPL1+CBLB+KLRD1+CLEC2B;CCL3L1+GABARAPL1+SLA+KLRD1+CLEC2B;CCL3L1+CBLB+SLA+KLRD1+CLEC2B;CCL3L1+LAG3+GABARAPL1+CBLB+SLA+KLRD1;CCL3L1+LAG3+GABARAPL1+CBLB+SLA+CLEC2B;CCL3L1+LAG3+GABARAPL1+CBLB+KLRD1+CLEC2B;CCL3L1+LAG3+GABARAPL1+SLA+KLRD1+CLEC2B;CCL3L1+LAG3+CBLB+SLA+KLRD1+CLEC2B;CCL3L1+GABARAPL1+CBLB+SLA+KLRD1+CLEC2B;CCL3L1+LAG3+GABARAPL1+CBLB+SLA+KLRD1+CLEC2B;LAG3;LAG3+GABARAPL1;LAG3+CBLB;LAG3+SLA;LAG3+KLRD1;LAG3+CLEC2B;LAG3+GABARAPL1+CBLB;LAG3+GABARAPL1+SLA;LAG3+GABARAPL1+KLRD1;LAG3+GABARAPL1+CLEC2B;LAG3+CBLB+SLA;LAG3+CBLB+KLRD1;LAG3+CBLB+CLEC2B;LAG3+SLA+KLRD1;LAG3+SLA+CLEC2B;LAG3+KLRD1+CLEC2B;LAG3+GABARAPL1+CBLB+SLA;LAG3+GABARAPL1+CBLB+KLRD1;LAG3+GABARAPL1+CBLB+CLEC2B;LAG3+GABARAPL1+SLA+KLRD1;LAG3+GABARAPL1+SLA+CLEC2B;LAG3+GABARAPL1+KLRD1+CLEC2B;LAG3+CBLB+SLA+KLRD1;LAG3+CBLB+SLA+CLEC2B;LAG3+CBLB+KLRD1+CLEC2B;LAG3+SLA+KLRD1+CLEC2B;LAG3+GABARAPL1+CBLB+SLA+KLRD1;LAG3+GABARAPL1+CBLB+SLA+CLEC2B;LAG3+GABARAPL1+CBLB+KLRD1+CLEC2B;LAG3+GABARAPL1+SLA+KLRD1+CLEC2B;LAG3+CBLB+SLA+KLRD1+CLEC2B;LAG3+GABARAPL1+CBLB+SLA+KLRD1+CLEC2B;GABARAPL1;GABARAPL1+CBLB;GABARAPL1+SLA;GABARAPL1+KLRD1;GABARAPL1+CLEC2B;GABARAPL1+CBLB+SLA;GABARAPL1+CBLB+KLRD1;GABARAPL1+CBLB+CLEC2B;GABARAPL1+SLA+KLRD1;GABARAPL1+SLA+CLEC2B;GABARAPL1+KLRD1+CLEC2B;GABARAPL1+CBLB+SLA+KLRD1;GABARAPL1+CBLB+SLA+CLEC2B;GABARAPL1+CBLB+KLRD1+CLEC2B;GABARAPL1+SLA+KLRD1+CLEC2B;GABARAPL1+CBLB+SLA+KLRD1+CLEC2B;CBLB;CBLB+SLA;CBLB+KLRD1;CBLB+CLEC2B;CBLB+SLA+KLRD1;CBLB+SLA+CLEC2B;CBLB+KLRD1+CLEC2B;CBLB+SLA+KLRD1+CLEC2B;SLA;SLA+KLRD1;SLA+CLEC2B;SLA+KLRD1+CLEC2B;KLRD1;KLRD1+CLEC2B;或CLEC2B。
在优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含以下,优选地由以下组成:表7至10中的任一个中公开的至少一种生物标志物组合(“特征”)或其任何组合,优选地表7中公开的至少一种生物标志物组合。在进一步优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含表7或8中公开的至少一种生物标志物组合,优选地由其组成,并且癌症是非原发性脑转移瘤。在进一步优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含表7或9中公开的至少一种生物标志物组合,优选地由其组成,并且癌症是肺癌。在进一步优选的实施方案中,鉴定反应性T细胞包括测定生物标志物组合的表达,该生物标志物组合包含以下,优选地由以下组成:表5的所有生物标志物+CD8B;表1和2的所有生物标志物+CD8B;表1的所有生物标志物+CD8B;表5和6的所有生物标志物+CD8B,并且癌症是神经胶质瘤。
技术人员知晓本文提及的生物标志物可以以来自不同等位基因的多种同工型表达,和/或可以表达为可以在细胞中经进一步加工的前体形式,例如在细胞内运输和/或分泌期间。此外,技术人员知晓来自非人物种的受试者将优选地表达上文所示的特定序列的同源物,其可以优选地通过序列比对和/或基于其的搜索算法,例如BLAST算法和适当的数据库,优选可公开获得的数据库来鉴定。优选地,指定的生物标志物的氨基酸序列与本文提及的特定生物生物标志物序列具有至少50%、更优选75%、还更优选85%、甚至更优选至少95%、甚至更优选至少98%、最优选至少99%同一性。
如本文所用,术语“受试者”涉及动物,优选脊椎动物,更优选哺乳动物,优选地涉及家畜,如牛、马、猪、绵羊或山羊,涉及伴侣动物,例如猫或犬,或涉及实验动物,如大鼠、小鼠或豚鼠。优选地,哺乳动物是灵长类动物,更优选猴,最优选人。优选地,受试者患有癌症,特别是在鉴定对受试者的癌细胞有反应的T细胞的方法的情况下。然而,还设想了受试者是表面上健康的受试者,优选至少50岁,更优选至少60岁,更优选至少70岁,甚至更优选至少80岁。
术语“样品”是指分离的细胞的样品或来自组织或器官、优选来自肿瘤的样品。因此,样品优选地包含或假定包含癌症识别淋巴细胞,优选T细胞。更优选地,样品包含或假定包含肿瘤浸润淋巴细胞(TIL)。还优选地,样品包含癌细胞,更优选肿瘤细胞。因此,样品优选包含TIL和癌细胞,优选是肿瘤样品。然而,样品还可以是非癌组织的样品,优选癌症邻近组织的样品,或外周血单核细胞(PBMC)的样品。如本领域技术人员所知,组织或器官样品可以通过以下方式从任何组织或器官获得:例如,活组织检查、手术或本领域技术人员认为合适的任何其他方法。分离的细胞可以通过分离技术(例如离心或细胞分选)从体液(例如淋巴液、血液、血浆、血清、液体等)获得,或从组织或器官获得。优选地,样品是包含细胞的组织或体液样品。优选地,样品是体液样品,优选血液样品。体液样品可以通过本领域技术人员熟知的常规技术从受试者获得,例如,静脉或动脉穿刺、灌洗或技术人员认为合适的任何其他方法。
有利的是,在本发明的基础工作中发现,使用生物标志物CCL4、CCL4L2、CCL3、CCL3L1和/或CXCL13,任选地包括另外的生物标志物,实现鉴定包含对细胞呈递的抗原有反应的TCR的T细胞,因此,特别适合于通过培养或通过在T细胞中表达相应的TCR来提供识别例如癌细胞的T细胞,例如用于癌症的细胞疗法。
上述定义经必要修改后适用于以下定义。以下进一步进行的另外定义和解释也适用于本说明书中所描述的所有实施方案(经必要修改)。
本发明还涉及鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中KLRD1和LAG3中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定反应性T细胞,
优选地,其中所述T细胞活化抗原是癌症抗原或自身免疫T细胞抗原,更优选是癌症抗原。
本发明进一步涉及鉴定与受试者的细胞、优选癌细胞上呈递的活化抗原结合的TCR的方法,所述方法包括
(A)根据鉴定反应性T细胞的方法鉴定反应性T细胞,
(B)提供步骤(A)中鉴定的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,
(C)鉴定与细胞上呈递的活化抗原结合的TCR。
优选地,鉴定TCR的方法是体外方法。除了与上文相关的步骤之外,该方法可以进一步包括另外的步骤。例如,另外的步骤可以涉及,例如,测定另外的核酸或氨基酸序列,或测定所述反应性T细胞的CD8和/或CD4表达。此外,所述步骤中的一个或多个可以由自动化设备进行或辅助。
术语“提供序列”,例如氨基酸序列和/或核酸序列,在本文中以广义使用,包括提供关于所述序列的信息或使得所述序列信息可获得的任何和所有方式和方法。因此,序列可以作为序列信息提供,优选地有形地嵌入在数据载体上。然而,序列还可以以包含所述序列的分子形式提供,优选地作为包含包含所述序列的TCRα和β链的TCR,更优选作为包含其的宿主细胞。如本领域技术人员所理解的,如果提供前述宿主细胞,则可以通过本领域技术人员已知的标准方法提供序列信息,例如对所述宿主细胞或其部分表达的TCR进行核酸测序。
术语“鉴定TCR”在本文中以广义使用,包括提供关于TCR的信息以实现至少测定其CDR序列的任何和所有方式和方法。因此,TCR不一定但可以以物理形式提供。因此,鉴定TCR可以包括提供TCR的至少CDR序列或至少编码所述CDR的多核苷酸的序列。优选地,所述序列是或曾经是通过基因表达的单细胞测定,优选地通过单细胞RNA测序来测定的,优选地如上文所指定的。然而,鉴定TCR还可以包括物理地提供所述TCR,例如通过提供表达所述TCR的宿主细胞,优选T细胞,或通过提供编码鉴定的TCR多肽的至少CDR的至少一种多核苷酸。如将理解的,在TCR是在自我复制实体(例如宿主细胞)的背景下提供的情况下,可能不需要提供TCR的至少CDR的氨基酸和/或编码其的多核苷酸的核酸复合体。
优选地,鉴定与活化抗原结合的TCR的方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR。更优选地,所述方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR,即优选地包括在宿主细胞中表达至少包含步骤B)中测定的CDR和至少一种辅助TCR多肽的TCR。
如本文所用,术语“包含至少CDR的TCR”涉及其中至少CDR是步骤B)中测定的那些的TCR,而TCR多肽的残余序列可以是一种或多种不同的α和β或γ和δ链的序列,例如异源序列。更优选地,TCR分子的可变区在步骤B)中提供并在步骤B1)中表达为TCR多肽的部分。然而,还设想了步骤B)中提供TCR多肽的另外的片段或完整TCR多肽的序列,并且任选地在步骤B1)中表达。如技术人员所理解的,还可能在步骤B)中提供比在步骤B1)中表达的更长的序列;例如,优选地,TCR多肽的可变区的氨基酸序列可以在步骤B)中提供,而在例如步骤B1)中异源TCR多肽的背景下,仅表达其CDR;或,可以在步骤B)中提供TCR多肽的可变区的氨基酸序列,并且在例如在步骤B1)中异源TCR多肽的背景下,可以表达抗原结合区的氨基酸序列。如果没有另外说明,TCR多肽优选表达为完整分子,即各自包含跨膜区、恒定区、连接区和可变区。
优选地,鉴定与呈递T细胞活化抗原的细胞结合的TCR的方法进一步包括步骤B2),其测定步骤B1)中表达的TCR与呈递在主要组织相容性复合体(MHC),优选MHC I类分子中复合的T细胞活化抗原(优选癌症抗原)的细胞的结合。测定TCR(优选地包括在TCR中)与在主要组织相容性复合体(MHC)分子中复合的T细胞活化抗原结合的方法是本领域已知的,并且包括,优选地,测定与携带可检测标记的MHC分子复合的T细胞活化抗原与TCR(其可以例如在宿主细胞的表面上表达)的结合。这种方法的熟知实例是四聚体测定,优选地使用与T细胞活化抗原复合的可溶性四聚体MHC分子。
优选地,鉴定与T细胞活化抗原结合的TCR的方法进一步包括步骤B3),其测定步骤B1)中表达的TCR对呈递所述T细胞活化抗原的细胞的识别。用于确定这种识别的测定是本领域已知的并且特别包括结合测定、活化测定和裂解测定。在所有这些测定中,优选地将呈递T细胞活化抗原的细胞与宿主细胞(例如表达至少包含指定的CDR的TCR的T细胞)共孵育。在结合测定中,确定癌细胞和前述宿主细胞是否彼此结合,优选地形成免疫突触,至少包括呈递T细胞活化抗原的细胞的MHC分子和TCR。在活化测定中,在所述共孵育后测试表达至少包含指定CDR的TCR的宿主细胞,优选T细胞的免疫活化生物标志物,例如干扰素-γ的产生。在裂解测定中,测定表达至少包含指定的CDR的TCR的宿主细胞,优选T细胞,在所述共孵育期间是否裂解呈递T细胞活化抗原的细胞的至少一部分。
优选地,鉴定与活化抗原结合的TCR的方法进一步包括步骤B4),其产生至少包含步骤B)中测定的CDR的可溶性TCR,并且测定所述可溶性TCR与癌细胞和/或与癌症抗原的结合,该癌症抗原在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。上文已描述了可溶性TCR。优选地,步骤B4)中使用携带可检测标记的可溶性TCR;因此,这种标记的可溶性TCR的结合可以例如通过荧光活化细胞分选设备进行检测。
优选地,在鉴定TCR的方法中,所述至少一种生物标志物的表达通过优选至少100个T细胞,更优选至少1000个T细胞的基因表达的单细胞测定进行测定。在这种情况下,可以提供步骤(B)的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列作为基因表达的单细胞测定的一部分,即编码所述CDR的mRNA可以作为基因表达的所述单细胞测定的一部分进行测序。优选地,在基因表达的单细胞测定之前预扩增相应的序列。然而,编码所述CDR的mRNA还可以在单独的测序步骤中测定,优选地通过使用适当的条形码方法。同样在前述情况下,该方法可以进一步包括步骤(B*1),其基于包括所述至少CDR序列的氨基酸序列的所述基因表达数据对T细胞进行聚类,以及进一步包括步骤(B*2),其与不表达所述至少一种生物标志物的聚类相比,选择在表达所述至少一种生物标志物的聚类中以增加的相对频率聚类的一个TCR或多个TCR。
本发明还涉及提供识别呈递T细胞活化抗原的细胞,优选癌细胞的T细胞的方法,所述方法包括
(i)根据本发明的方法鉴定与呈递T细胞活化抗原的细胞结合的TCR,
(ii)在T细胞中表达至少包含步骤(I)的TCR的互补决定区(CDR)的TCR,并且,由此,
(iii)提供识别呈递T细胞活化抗原的细胞,优选癌细胞的T细胞。
优选地,提供T细胞的方法是体外方法,其中一个或多个步骤可以由自动化设备进行或辅助。
除了与上文相关的步骤之外,该方法可以包括另外的步骤。例如,另外的步骤可以涉及,例如,将至少编码步骤(i)的TCR的CDR的多核苷酸克隆到TCRα、β、γ或δ链主链中,或将编码步骤(i)的TCR多肽的可变区的多核苷酸克隆到TCRα和β或TCRγ和δ链主链,优选地在至少一种表达载体上;或将编码TCR多核苷酸的多核苷酸克隆到一种或多种表达载体中。如技术人员将理解的,TCRα链的CDR和/或可变区将优选地克隆到TCRα链主链中;优选地将TCRβ链的CDR和/或可变区克隆到TCRβ链主链中。前述内容经修改后适用于γ链和δ链。该方法还可以包括扩增、优选克隆扩增识别癌细胞的T细胞的另外的步骤,以提供识别癌细胞的T细胞的细胞制剂。因此应当理解,识别癌细胞的T细胞可以是步骤(i)中鉴定的T细胞或其克隆衍生物(即子细胞)。
优选地,提供T细胞的方法进一步包括测试步骤(ii)的T细胞对呈递活化剂的细胞(例如癌细胞)的反应性的步骤。如本文所用,术语“测试T细胞的反应性”包括技术人员认为适合测定指定的T细胞是否具有反应性的每一种方法。用于测试反应性的优选方法已在上文中描述,例如测定T细胞的结合、活化和/或呈递活化抗原的细胞(例如癌细胞)的裂解。
本发明进一步涉及通过如上文指定的鉴定对呈递T细胞活化抗原的细胞(优选癌细胞)有反应的T细胞的方法鉴定的,和/或通过提供识别如上文指定的呈递T细胞活化抗原的细胞的T细胞的方法获得或可获得的反应性T细胞,其用于医学,特别是用于治疗和/或预防受试者的癌症或自身免疫性疾病,该反应性T细胞优选地包含包含SEQ ID NO:1和/或SEQID NO:2的氨基酸序列的T细胞受体,其优选地分别由包含SEQ ID NO:3和/或4的多核苷酸编码。
术语“治疗(treating和treatment)”是指显著改善本文提及的疾病或病症或伴随其的症状。如本文所用,所述治疗还包括相对于本文提及的疾病或病症的完全恢复健康。应当理解,本文所用的术语“治疗”可能并非对所有待治疗的受试者均有效。然而,该术语优选地要求可以成功治疗患有本文提及的疾病或病症的受试者中的统计学显著部分。本领域技术人员可以使用各种熟知的统计评价工具(例如,置信区间的确定、p值确定、Student t检验、Mann-Whitney检验等)毫不费力地确定一部分是否具有统计学显著性。优选的置信区间是至少90%、至少95%、至少97%、至少98%或至少99%。p值优选为0.1、0.05、0.01、0.005或0.0001。优选地,治疗应对给定队列或群体的至少10%、至少20%、至少50%、至少60%、至少70%、至少80%或至少90%的受试者有效。优选地,治疗癌症是减少受试者的肿瘤负荷。如技术人员将理解的,例如癌症的治疗有效性取决于多种因素,包括,例如癌症分期和癌症类型。
术语“预防”是指在受试者中保持相对于本文所提及的疾病或病症的健康一段时间。应当理解,所述时间段可以取决于已施用的药物化合物的量和本说明书其他地方讨论的受试者的个体因素。应当理解,预防可能并非对用本发明化合物治疗的所有受试者均有效。然而,该术语优选地要求队列或群体的统计学显著部分的受试者被有效预防患有本文提及的疾病或病症或其伴随症状。优选地,在该背景下设想受试者队列或群体,通常,即,如果没有根据本发明的预防措施,将出现本文提及的疾病或病症。本领域技术人员可以使用本说明书其他地方讨论的各种熟知的统计学评价工具毫不费力地来确定部分是否具有统计学显著性。
本发明还涉及药物组合物,其包含通过上文指定的方法鉴定的和/或通过提供识别呈递上文指定的活化抗原的细胞的T细胞的方法获得或可获得的反应性T细胞,优选地包含T细胞受体,该T细胞受体包含SEQ ID NO:1和/或SEQ ID NO:2的氨基酸序列。
如本文所用,术语“药物组合物”涉及包含如本文指定的药学上可接受的形式的一种或多种化合物(包括宿主细胞,特别是T细胞)和药学上可接受的载体的组合物。可以将化合物和/或赋形剂配制成药学上可接受的盐。可接受的盐包含乙酸盐、甲酯、HCl、硫酸盐、氯化物等。药物组合物优选地外用或全身施用,优选地静脉内或瘤内施用。这些化合物可以与其他药物以共同的药物组合物或作为单独的药物组合物联合施用,其中所述单独的药物组合物可以以试剂盒部分的形式提供。特别地,可以设想共同施用佐剂。
优选地,化合物以常规剂型施用,该剂型通过根据常规程序将宿主细胞或药物与标准药物载体组合而制备。这些程序可以涉及混合、分散或溶解适合期望制剂的成分。应当理解,药学上可接受的载体或稀释剂的形式和特性由与其组合的活性成分的量、施用途径和其他熟知的变量决定。
载体在与制剂的其他成分相容并且对其接受者无害的意义上必须是可接受的。所采用的药物载体可以是,例如,固体、凝胶或优选液体。液体载体的实例是磷酸盐缓冲盐水溶液、水、乳液、各种类型的润湿剂、无菌溶液等。合适的载体包括上文提到的那些和本领域熟知的其他载体,参见,例如,Remington′s Pharmaceutical Sciences,Mack出版公司,伊斯顿,宾夕法尼亚州。优选地选择稀释剂以便不影响T细胞的生物活性和潜在的另外的药物活性成分。这种稀释剂的实例有蒸馏水、生理盐水、林格溶液、葡萄糖溶液和Hank's溶液。此外,药物组合物或制剂还可以包括其他载体、佐剂或无毒、非治疗性、非免疫原性稳定剂等。
治疗有效剂量是指用于本发明的药物组合物中的化合物的量,其预防、改善或治疗本文提及的病况。化合物的治疗功效和毒性可以通过细胞培养物或实验动物中的标准制药程序来测定,例如,通过测定ED50(对50%的群体治疗有效的剂量)和/或LD50(对50%的群体致死的剂量)。治疗作用与毒性作用之间的剂量比是治疗指数,并且其可以用LD50/ED50的比值表示。
剂量方案将由主治医师确定,优选地考虑相关临床因素,并且优选地,根据本文其他地方描述的方法中的任何一种。如医学领域所熟知的,任何一名患者的剂量可能取决于许多因素,包括患者的体型、体表面积、年龄、待施用的具体化合物、性别、施用时间和途径、一般健康状况以及同时施用的其他药物。可以通过定期评估来监测进展情况。典型的剂量可以是,例如,104至109个宿主细胞的范围;然而,可以预见低于或高于该示例性范围的剂量,特别是考虑到前述因素。本文提及的药物组合物和制剂施用至少一次以治疗或预防本说明书中所述的疾病或病况。然而,所述药物组合物可以施用超过一次,例如,优选一次至四次,更优选两次或三次。
本发明还涉及编码与活化抗原结合的至少一种TCR的多核苷酸,该TCR是根据本文指定的鉴定与活化抗原结合的TCR的方法提供的或可鉴定的。
术语“多核苷酸”是技术人员已知的。如本文所用,该术语包括包含如本文指定的一个或多个核酸序列或由其组成的核酸分子。本发明的多核苷酸应优选地作为分离的多核苷酸(即从其天然背景中分离)或以基因修饰的形式提供。多核苷酸,优选地,是DNA,包括cDNA,或是RNA。该术语涵盖单链以及双链多核苷酸。优选地,多核苷酸是嵌合分子,即,优选地,包含与剩余核酸序列异源的至少一种核酸序列,优选至少20bp,更优选至少100bp。此外,优选地,还包含化学修饰的多核苷酸,包括天然存在的修饰的多核苷酸,例如糖基化或甲基化的多核苷酸,或人工修饰的多核苷酸,例如生物素化的多核苷酸。
本发明还涉及鉴定反应性T细胞的至少一种生物标志物的方法,其包括
(I)提供受试者样品中T细胞的多种生物标志物的表达数据,
(II)基于步骤(A)的生物标志物的表达,提供对所述多个T细胞的聚类;
(III)提供步骤(B)的T细胞的TCR链的至少互补决定区(CDR)的氨基酸序列;
(IV)确定包含步骤(C)的互补决定区(CDR)的TCR对癌细胞的识别;
(V)针对另外的T细胞重复步骤(C)和(D)至少一次,所述另外的T细胞与步骤(D)中其TCR被测定为识别呈递T细胞活化抗原的细胞聚类,
(VI)测定步骤(B)的至少一个聚类,其包含最高分数的的T细胞,该T细胞包含识别呈递T细胞活化抗原的细胞的T细胞受体;和
(VII)测定由步骤(F)中测定的聚类中最高分数的T细胞表达的至少一种生物标志物,从而鉴定反应性T细胞的至少一种生物标志物。
优选地,本发明的方法是体外方法。此外,它还可以包括除了以上明确提到的那些之外的步骤。此外,所述步骤中的一个或多个可以由自动化设备辅助或进行。
术语“提供表达数据”和“提供氨基酸序列”被技术人员理解为包括使相应数据可获得的每一种和每个方式。此类数据可以从现存数据库、优选表达数据库提供。优选地,提供T细胞的多种生物标志物的表达数据包括测定所述生物标志物的表达,例如,通过根据本领域已知的方法将源自其的RNA或cDNA与表达阵列杂交。如本文所提及的,提供表达数据是提供单个细胞的表达数据,即分别提供每个细胞的生物标志物的表达数据,从而实现识别由T细胞表达的生物标志物集。因此,表达数据优选通过基因表达的单细胞测定来测定,更优选通过单细胞RNA测序来测定,如本文其他地方所指定的。优选地,表达数据包含由所述T细胞表达的TCR的至少CDR的序列。优选地,表达数据包含T细胞活化生物标志物和/或上文指定的生物标志物的表达数据。
术语“提供聚类”涉及将个体T细胞分配到共享相似的表达生物标志物集的聚类中。所述聚类优选地通过本领域已知的算法以计算机实现的方式执行,例如基于图的聚类或k均值聚类MacQueen(1967),“多变量观测值分类和分析的一些方法(Some methods forclassification and analysis of multivariate observations)”,第五届伯克利数理统计和概率研讨会。聚类可以通过本领域已知的方法可视化,例如tSNE(van der Maaten和Hinton(2008),J Machine Learning Res 9:2579)或UMAP(McInnes等人(2020),arXiv:1802.03426v3),优选UMAP。然而,还可以使用其他聚类方法。优选地,多个聚类,即提供至少两个,优选至少五个,更优选至少十个,还更优选至少25个。优选地,聚类,即聚类步骤的结果,具有受试者特异性。
术语“测定至少一个聚类”是本领域技术人员所理解的。根据该方法的步骤(II),提供聚类,优选地提供至少两个聚类;根据步骤(IV),评价至少两个聚类的成员是否是反应性T细胞,并且根据步骤(VI),测定至少一个聚类包含最高分数的包含识别呈递T细胞活化抗原的细胞的T细胞受体的T细胞。如技术人员理解的,该步骤优选地鉴定包含反应性T细胞的聚类,而不需要最初知晓哪些生物标志物指示反应性T细胞。一旦鉴定出聚类,优选地假定同一聚类的其他T细胞成员也具有癌症反应性。还应当理解,重复步骤(III)和(IV)至少一次,优选至少两次,更优选至少三次,实现进一步细化聚类定义。优选地假定最终鉴定的聚类中以最高频率表达的生物标志物是癌症反应性T细胞的生物标志物。
本发明进一步公开并提出了包括计算机可执行指令的计算机程序,用于当该程序在计算机或计算机网络上执行时,执行本文所附的一个或多个实施方案中的根据本发明的方法。具体地,计算机程序可以存储在计算机可读数据载体上。因此,具体地,如上所述的方法步骤a)至d)中的一个、多于一个或甚至全部可以通过使用计算机或计算机网络、优选地通过使用计算机程序来执行。
本发明进一步公开并提出了具有程序代码装置的计算机程序产品,以当程序在计算机或计算机网络上执行时,执行本文所附的一个或多个实施方案中的根据本发明的方法。具体地,程序代码装置可以存储在计算机可读数据载体上。此外,本发明公开并提出了其上存储有数据结构的数据载体,该数据载体在加载到计算机或计算机网络中之后,例如进入计算机或计算机网络的工作存储器或主存储器,可以执行根据本文公开的一个或多个实施方案的方法。
本发明进一步提出并公开了计算机程序产品,其具有存储在机器可读载体上的程序代码装置,以当程序在计算机或计算机网络上执行时,执行根据本文公开的一个或多个实施方案的方法。如本文所用,计算机程序产品是指作为可交易产品的程序。产品通常可以以任何形式存在,例如以纸质形式,或在计算机可读数据载体上。具体地,计算机程序产品可以通过数据网络分布。
最后,本发明提出并公开了调制数据信号,其包含计算机系统或计算机网络可读的指令,用于执行根据本文公开的一个或多个实施方案的方法。
优选地,参考本发明的计算机实现的方面,根据本文公开的一个或多个实施方案的方法的一个或多个方法步骤甚至全部方法步骤可以利用计算机或计算机网络来执行。因此,通常,包括数据的提供和/或操纵的任何方法步骤可以通过使用计算机或计算机网络来执行。通常,这些方法步骤可以包括任何方法步骤,通常除了需要手动工作的方法步骤之外,例如提供样品和/或执行实际测量的某些方面。
具体地,本发明进一步公开了:
-计算机或计算机网络,其包括至少一个处理器,其中该处理器适合于执行根据本说明书中所描述的实施方案中的一个的方法,
-计算机可加载的数据结构,其适合于在该数据结构在计算机上执行时,执行根据本说明书中描述的实施方案中的一个的方法,
-计算机程序,其中该计算机程序适合于在该程序在计算机上执行时,执行根据本说明书中描述的实施方案中的一个的方法,
-计算机程序,其包括用于在计算机程序在计算机上或在计算机网络上执行时,执行根据本说明书中描述的实施方案中的一个的方法的程序装置,
-计算机程序,其包括根据前述实施方案的程序装置,其中所述程序装置存储在计算机可读的存储介质上,
-存储介质,其中数据结构存储在存储介质上,并且其中数据结构适合于在已被加载到计算机或计算机网络的主和/或工作存储器中之后,执行根据本说明书中描述的实施方案中的一个的方法,和
-具有程序代码装置的计算机程序产品,其中该程序代码装置可以被存储或存储在存储介质上,用于执行根据本说明书中描述的实施方案中的一个的方法,如果该程序代码装置在计算机或计算机网络上。
综上所述,具体设想如下实施方案:
实施方案1:一种鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定反应性T细胞,
优选地,其中所述T细胞活化抗原是癌症抗原或自身免疫T细胞抗原,更优选是癌症抗原。
实施方案2:一种鉴定对癌细胞有反应的T细胞(癌症反应性T细胞)的方法,其包括
(a)测定来自受试者的样品的T细胞中CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定癌症反应性T细胞。
实施方案2:实施方案1或2的方法,其中步骤(a)包括测定CCL4、CCL4L2、CCL3、CCL3L1和CXCL13中的至少两种、优选至少三种、更优选至少四种的表达。
实施方案4:实施方案1至3中任一项的方法,其中步骤(a)进一步包括测定选自由以下组成的列表的至少一种生物标志物的表达:IFNG、HAVCR2、FNBP1、CSRNP1、SPRY1、RHOH、FOXN2、HIF1A、TOB1、RILPL2、CD8B、GABARAPL1、TNFSF14、EGR1、EGR2、TAGAP、TNFSF9、ANXA1、MAP3K8、PIK3R1、DUSP2、DUSP4、DUSP6、CLIC3、RASGEF1B、LAG3、XCL2、NR4A2、DNAJB6、NFKBID、MCL1、EVI2A、SLC7A5、H3F3B、NR4A3、REL、IRF4、CST7、ATF3、TNF、GPR171、BCL2A1、ITGA1、TNFAIP3、NR4A1、RUNX3、HERPUD2、FASLG、CBLB、PTGER4、SLA、XCL1、BHLHE40、LYST、KLRD1、ZNF682、CTSW、SLC2A3、NLRP3、SCML4、VSIR、LINC01871和ZFP36L1。
实施方案5:实施方案1至4中任一项的方法,其中在步骤(a)中通过基因表达的单细胞测定,优选通过单细胞RNA测序测定表达和/或其中所述样品是肿瘤样品。
实施方案6:一种鉴定与受试者的细胞,优选癌细胞上呈递的活化抗原结合的TCR的方法,所述方法包括
(A)根据实施方案1至5中任一项的方法鉴定反应性T细胞,
(B)提供步骤(A)中鉴定的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,
(C)鉴定与细胞上呈递的活化抗原结合的TCR。
实施方案7:实施方案1至6中任一项的方法,其中步骤a)的至少一种生物标志物和/或步骤(B)中的核酸序列通过单细胞测序、优选通过单细胞RNA测序来测定。
实施方案8:实施方案6或7的方法,其中所述方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR。
实施方案9:实施方案6至8中任一项的方法,其中所述方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR。
实施方案10:实施方案9的方法,其中所述方法进一步包括步骤B2),其优选地在四聚体测定中,测定步骤B1)中表达的TCR与细胞上呈递的活化抗原(优选癌症抗原)的结合,该活化抗原在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。
实施方案11:实施方案9或10的方法,其中所述方法进一步包括步骤B3),其测定步骤B1)中表达的TCR对呈递T细胞活化抗原的细胞的识别。
实施方案12:实施方案6至11中任一项的方法,其中所述方法进一步包括步骤B4),其产生至少包含步骤B)中测定的CDR的可溶性TCR,并且测定所述可溶性TCR与T细胞活化抗原的结合;优选与主要组织相容性复合体(MHC)、优选MHC I类分子复合的癌症抗原的结合。
实施方案13:一种提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞的方法,所述方法包括
(i)根据实施方案6至12中任一项的方法鉴定与呈递T细胞活化抗原的细胞结合的TCR,
(ii)在T细胞中表达至少包含步骤(I)的TCR的互补决定区(CDR)的TCR,并且,由此,
(iii)提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞。
实施方案14:实施方案13的方法,其中所述方法进一步包括测试步骤(ii)的T细胞对呈递T细胞活化抗原的细胞的反应性的步骤。
实施方案15:实施方案1至14中任一项的方法,其中所述样品是组织样品或体液样品。
实施方案16:实施方案1至15中任一项的方法,其中所述样品是血液样品。
实施方案17:实施方案1至16中任一项的方法,其中所述样品是癌症样品。
实施方案18:实施方案1至17中任一项的方法,其中所述样品是非癌组织、优选癌症邻近组织的样品。
实施方案19:通过根据实施方案1至5中任一项的方法鉴定的和/或通过根据实施方案13或14的方法获得的或可获得的反应性T细胞,其用于医学,该反应性T细胞优选地包含T细胞受体,该T细胞受体包含SEQ ID NO:1和/或SEQ ID NO:2的氨基酸序列。
实施方案20:通过根据实施方案1至5中任一项的方法鉴定的和/或通过根据实施方案13或14的方法获得的或可获得的反应性T细胞,其用于治疗和/或预防受试者的癌症,该反应性T细胞优选地包含T细胞受体,该T细胞受体包含SEQ ID NO:1和/或SEQ ID NO:2的氨基酸序列。
实施方案21:实施方案1至20中任一项的主题,其中所述受试者是表面上健康的受试者。
实施方案22:实施方案1至21中任一项的主题,其中所述受试者是患有癌症的受试者。
实施方案23:实施方案1至22中任一项的主题,其中所述呈递T细胞活化抗原的细胞是癌细胞,优选肿瘤细胞。
实施方案24:一种鉴定反应性T细胞的至少一种生物标志物的方法,其包括
(I)提供受试者的样品中T细胞的多种生物标志物的表达数据,
(II)基于步骤(I)的生物标志物的表达,提供对所述多个T细胞的聚类;
(III)提供步骤(II)的T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;
(IV)测定表达包含步骤(III)的CDR的TCR的T细胞与呈递T细胞活化抗原的细胞的反应性;
(V)针对另外的T细胞重复步骤(III)和(IV)至少一次,所述另外的T细胞与步骤(IV)中测定的TCR对呈递T细胞活化抗原的细胞有反应的T细胞聚类,其中所述另外的T细胞的TCR与步骤(IV)的TCR不相同;
(VI)测定步骤(II)的至少一个聚类,其包含最高分数的的T细胞,该T细胞包含识别呈递T细胞活化抗原的细胞的T细胞受体;和
(VII)测定由步骤(VI)中确定的聚类中最高分数的T细胞表达的至少一种生物标志物,从而鉴定癌症反应性T细胞的至少一种生物标志物。
实施方案25:前述实施方案中任一项的主题,其中所述T细胞或多个T细胞是CD8+T细胞或CD4+ T细胞,优选是CD8+ T细胞。
实施方案26:前述实施方案中任一项的主题,其中所述TCR包含TCRα链和TCRβ链或TCRγ链和TCRδ链,优选地由它们组成,优选地包含TCRα链和TCRβ链,更优选由它们组成。
实施方案27:编码根据实施方案6至12中任一项的方法提供的或可鉴定的与活化抗原结合的至少一种TCR的多核苷酸。
实施方案28:前述实施方案中任一项的主题,其中所述反应性T细胞是癌症反应性T细胞。
实施方案29:实施方案1至3中任一项的方法,其中步骤(a)进一步包括测定选自由LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B组成的列表中的至少一种生物标志物的表达,优选地包括测定实施方案1和/或实施方案29的所有生物标志物。
实施方案30:实施方案1至3和29中任一项的方法,其中步骤(a)进一步包括测定选自由以下组成的列表中的至少一种生物标志物的表达:CTSD、CD7、CD3D、LSP1、SNAP47、GAPDH、KLRK1、TNS3、VCAM1、KLRC2、PMAIP1、FYN、CTLA4、GSTP1、AREG、FAM3C、SH3BGRL3、CD3E、SRGAP3、SRGN、SIRPG、SCPEP1、RHOB、ANKRD28、LINC02446、RABAC1、IKZF3、BCAS4、CD2、BLOC1S1、RHOA、EID1、MYL6、CLIC1、IQGAP1、ARPC2、PHYKPL、PRDM1、EVL、TPI1、ADGRE5、PAXX、RGS2、HERPUD1、IFI27L2、SEPTIN7、UBB、JUN、CFLAR、LITAF、ANXA5、STAT3、RSRP1、PRDX5、SEM1、SER-PINB1、RNF19A、IL2RG、ENSA、SRP14、ATP6V0C、LY6E、BIN1、AKAP13、PDE4D、PELI1、PARK7、MSN、SERTAD1、RAC2、SELENOH、PSMB8、CKLF、KLRC1、RNASEK、MT2A、TXNIP和FOXP3。
实施方案31:实施方案1至3和29至30中任一项的方法,其中步骤(a)包括测定至少以下的表达:CCL3L1+CCL3;CCL3L1+CCL3+LAG3+KLRD1;CCL3L1+CCL3+CXCL13;CCL3L1+CCL3+CXCL13+KLRD1;CCL3L1+CCL3+CXCL13+LAG3;CCL3L1+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL3+KLRD1;CCL3L1+CCL3+LAG3;CCL3L1+CCL4+CCL3;CCL3L1+CCL4+CCL3+CXCL13;CCL3L1+CCL4+CCL3+CXCL13+KLRD1;CCL3L1+CCL4+CCL3+CXCL13+LAG3;CCL3L1+CCL4+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL3+LAG3;CCL3L1+CCL4+CCL3+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+LAG3;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+KLRD1;CCL3L1+CCL4+CCL4L2+CXCL13;CCL3L1+CCL4+CCL4L2+CXCL13+KLRD1;CCL3L1+CCL4+CCL4L2+CXCL13+LAG3;CCL3L1+CCL4+CCL4L2+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+LAG3+KLRD1;CCL3L1+CCL4+CXCL13;CCL3L1+CCL4+CXCL13+KLRD1;CCL3L1+CCL4+CXCL13+LAG3;CCL3L1+CCL4+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+KLRD1;CCL3L1+CCL4+LAG3+KLRD1;CCL3L1+CCL4L2+CCL3;CCL3L1+CCL4L2+CCL3+CXCL13;CCL3L1+CCL4L2+CCL3+CXCL13+KLRD1;CCL3L1+CCL4L2+CCL3+CXCL13+LAG3;CCL3L1+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4L2+CCL3+KLRD1;CCL3L1+CCL4L2+CCL3+LAG3+KLRD1;CCL3L1+CCL4L2+CXCL13;CCL3L1+CCL4L2+CXCL13+KLRD1;CCL3L1+CCL4L2+CXCL13+LAG3;CCL3L1+CCL4L2+CXCL13+LAG3+KLRD1;CCL3L1+CCL4L2+KLRD1;CCL3L1+CCL4L2+LAG3;CCL3L1+CCL4L2+LAG3+KLRD1;CCL3L1+CXCL13;CCL3L1+CXCL13+KLRD1;CCL3L1+CXCL13+LAG3;CCL3L1+CXCL13+LAG3+KLRD1;CCL3L1+LAG3+KLRD1;CCL3+CXCL13;CCL3+CXCL13+KLRD1;CCL3+CXCL13+LAG3;CCL3+CXCL13+LAG3+KLRD1;CCL3+LAG3+KLRD1;CCL4+CCL3;CCL4+CCL3+CXCL13;CCL4+CCL3+CXCL13+KLRD1;CCL4+CCL3+CXCL13+LAG3;CCL4+CCL3+CXCL13+LAG3+KLRD1;CCL4+CCL3+KLRD1;CCL4+CCL3+LAG3+KLRD1;CCL4+CCL4L2+CCL3+CXCL!3;CCL4+CCL4L2+CCL3+CXCL13+KLRD1;CCL4+CCL4L2+CCL3+CXCL13+LAG3;CCL4+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL4+CCL4L2+CCL3+KLRD1;CCL4+CCL4L2+CCL3+LAG3;CCL4+CCL4L2+CXCL13;CCL4+CCL4L2+CXCL13+KLRD1;CCL4+CCL4L2+CXCL13+LAG3;CCL4+CCL4L2+CXCL13+LAG3+KLRD1;CCL4+CCL4L2+KLRD1;CCL4+CCL4L2+LAG3+KLRD1;CCL4+CXCL13;CCL4+CXCL13+KLRD1;CCL4+CXCL13+LAG3;CCL4+CXCL13+LAG3+KLRD1;CCL4+LAG3+KLRD1;CCL4L2+CCL3;CCL4L2+CCL3+CXCL13;CCL4L2+CCL3+CXCL13+KLRD1;CCL4L2+CCL3+CXCL13+LAG3;CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL4L2+CCL3+KLRD1;CCL4L2+CCL3+LAG3+KLRD1;CCL4L2+CXCL13;CCL4L2+CXCL13+KLRD1;CCL4L2+CXCL13+LAG3;CCL4L2+CXCL13+LAG3+KLRD1;CCL4L2+LAG3+KLRD1;CXCL13+LAG3;CXCL13+LAG3+KLRD1;KLRD1;KLRD1+CCL3;KLRD1+CCL3L1;KLRD1+CCL4L2;KLRD1+CXCL13;KLRD1+LAG3;表1的所有生物标志物;表5的所有生物标志物;或表6的所有生物标志物。
实施方案32:实施方案1至3和29至31中任一项的方法,其中所述T细胞活化抗原是癌症抗原,并且其中优选地所述样品是肿瘤样品。
实施方案33:实施方案32的方法,其中所述癌症是非脑原发性肿瘤的脑转移、是肺癌或是成胶质细胞瘤,优选地是非脑原发性肿瘤的脑转移或是肺癌。
实施方案34:一种鉴定与受试者的细胞、优选癌细胞上呈递的T细胞活化抗原结合的TCR的方法,所述方法包括
(A)根据实施方案1至3和29至33中任一项的方法鉴定反应性T细胞,
(B)提供步骤(A)中鉴定的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,
(C)鉴定与细胞上呈递的活化抗原结合的TCR。
实施方案35:实施方案1至3和29至34中任一项的方法,其中步骤a)的至少一种生物标志物的表达和/或编码步骤(B)的氨基酸序列的核酸序列通过单细胞测序,优选地通过单细胞RNA测序来测定。
实施方案36:实施方案34或35的方法,其中所述方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR。
实施方案37:实施方案36的方法,其中所述方法进一步包括步骤B2),其优选在四聚体测定中,测定步骤B1)中表达的TCR与T细胞活化抗原的结合,该T细胞活化抗原在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。
实施方案38:实施方案36或37的方法,其中所述方法进一步包括步骤B3),其测定步骤B1)中表达的TCR对呈递T细胞活化抗原的细胞的识别。
实施方案39:实施方案34至38中任一项的方法,其中所述方法进一步包括步骤B4),其产生至少包含步骤B)中测定的CDR的可溶性TCR,并且测定所述可溶性TCR与癌细胞和/或与癌症抗原的结合,所述癌症抗原在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。
实施方案40:一种提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞的方法,所述方法包括
(i)根据实施方案34至36中任一项的方法鉴定与呈递T细胞活化抗原的细胞结合的TCR,
(ii)在T细胞中表达至少包含步骤(I)的TCR的互补决定区(CDR)的TCR,并且,由此,
(iii)提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞。
实施方案41:通过根据实施方案1至3和29至33中任一项的方法鉴定的和/或通过根据实施方式34至40中任一项的方法获得的或可获得的反应性T细胞,其用于医学或用于治疗和/或预防受试者的癌症,该反应性T细胞优选地包含T细胞受体,该T细胞受体包含SEQID NO:1和/或SEQ ID NO:2的氨基酸序列。
实施方案42:一种鉴定反应性T细胞的至少一种生物标志物的方法,其包括
(I)提供受试者的样品中T细胞的多种生物标志物的表达数据,
(II)基于步骤(I)的生物标志物的表达,提供对所述多个T细胞的聚类;
(III)提供步骤(II)的T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;
(IV)测定表达包含步骤(III)的CDR的TCR的T细胞对呈递T细胞活化抗原的细胞的反应性;
(V)针对另外的T细胞重复步骤(III)和(IV)至少一次,所述另外的T细胞与步骤(IV)中测定的TCR对呈递T细胞活化抗原的细胞有反应的T细胞聚类,其中所述另外的T细胞的TCR与步骤(IV)的TCR不相同;
(VI)测定步骤(II)的至少一个聚类,其包含最高分数的T细胞,该T细胞包含识别呈递T细胞活化抗原的细胞的T细胞受体;和
(VII)测定由步骤(VI)中测定的聚类中最高分数的T细胞表达的至少一种生物标志物,从而鉴定癌症反应性T细胞的至少一种生物标志物。
实施方案43:实施方案1至3和29至42中任一项的主题,其中所述T细胞或多个T细胞是CD8+ T细胞或CD4+ T细胞,优选是CD8+ T细胞。
实施方案44:实施方案34至43中任一项的主题,其中所述TCR包含TCRα链和TCRβ链,优选地由TCRα链和TCRβ链组成。
实施方案44:一种鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中KLRD1和LAG3中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定反应性T细胞,
优选地,其中所述T细胞活化抗原是癌症抗原或自身免疫T细胞抗原,更优选是癌症抗原。
实施方案45:实施方案44的主题,进一步包括实施方案1至43中任一项的至少一个特征。
本说明书中引用的所有参考文献的全部公开内容以及本说明书中具体提及的公开内容均通过引用并入本文。
图例
图1:A)和B)分别显示了2名患者的T细胞UMAP聚类结果。D)-F)和图G)-J)分别显示了患者1(D)-F))和患者2(G)-J))的聚类细胞中核心基因CCL3、CCL3L1、CCL4和CCL4L2的表达,(K)显示了患者2中核心基因CXCL13的表达。
图2:显示了基于患者1(A))和患者2(B)的核心基因CCL3、CCL3L1、CCL4和CCL4L2的表达定义的癌症反应性T细胞聚类,而C)显示了基于患者2中表达核心基因CXCL13定义的癌症反应性T细胞聚类。
图3:A)显示了患者1的转录组聚类(Y轴)中选定的TCR克隆(X轴)的分布。B)显示了基于反应聚类中TCR分数的TCR聚类,以及C)显示了基于FACS的测定的TCR检测结果。
图4:A)显示了患者2的转录组聚类(Y轴)中选定的TCR克隆(X轴)的分布。B)显示了基于反应聚类中TCR分数的TCR聚类,以及C)显示了基于NFAT报告基因测定的TCR测试结果:TCR转基因Jurkat细胞与负载肽的自体PBMC共培养证实TCR4识别肿瘤表达的IDH1.R132H突变表位。数据描述为3次技术重复的平均值+SD。3次独立实验的代表。CD3+CD28刺激代表T细胞的最大可能活化。MOG是阴性对照肽,其在测定中不与任一TCR结合。
图5:A)流程概述;从肿瘤材料中分离患者T细胞,并测定其转录组和VDJ序列;使用分类器,可以鉴定具有“反应特征”的T细胞,任选地使用UMAP上的多种标志物;b)图1B:体外测试结果实例。
图6:A)患者3(非原发性脑转移)的测试数据;黑点表示反应性T细胞,亮灰色点表示未测试的T细胞,深灰色点表示测试后无反应性的T细胞;实线多边形表示测试的反应性T细胞聚类的区域,虚线多边形表示测试的非反应性T细胞聚类的比较区域。B)-E)使用5个核心基因(B)、7个可选的核心基因(C)、核心和辅助基因(D)、特征2基因(E)预测反应性TCR;F)和G)是分别使用Lowery等人(2022)(F)和WO 2021/188954A1(G)中鉴定的生物标志物的比较实施例;H)-L):患者3的核心基因H)CCL3L1、I)CCL3、J)CCL4、K)CCL4L2和L)CXCL13的表达。
图7:A)患者2(神经胶质瘤)的测试数据;黑点表示反应性T细胞,亮灰色点表示未测试的T细胞,深灰色点表示测试后无反应性的T细胞;B)-E)使用5个核心基因(B)、7个可选的核心基因(C)、核心和辅助基因(D)以及特征2基因(E)预测反应性TCR;F)和G)是分别使用Lowery等人(2022)(F)和WO 2021/188954 A1(G)中鉴定的生物标志物的比较实施例。
图8:A)有关肺癌反应性T细胞的外部数据;黑点表示反应性T细胞,亮灰点表示未测试的T细胞;B)-E)和H)使用5个核心基因(B)、7个可选核心基因(C)、核心和辅助基因(D)、特征2基因((E)和单独的CCL3L1(H)预测反应性TCR;F)和G)是分别使用Lowery等人(2022)(F)和WO 2021/188954 A1(G)中鉴定的生物标志物的比较实施例。
以下实施例仅用于说明本发明。无论如何,它们不应被解释为限制本发明的范围。
实施例1:单细胞文库制备
对肿瘤的单细胞悬浮液进行CD45+CD3+群的FACS分选以富集T细胞。根据生产商的方案,使用Chromium单细胞免疫分析试剂盒(Chromium Single Cell Immune ProfilingKit)(10X Chromium)进行分选T细胞的单细胞文库构建。然后,将构建的scVDJ和scRNA文库分别在Hiseq2500 Rapid/Nextseq550和Hiseq4000(Illumina)上进行测序。
实施例2:单细胞RNA分析
测序原始数据使用cellranger pipeline(v3.1.0)进行处理,并使用默认设置进行相应的GRCh38基因组组装,以生成基因表达矩阵。将矩阵导入R并使用Seurat包进行分析。为了进行质量控制,基于UMI、基因数量和线粒体基因表达百分比去除异常值。然后,转换并归一化基因表达,然后从可变基因中去除VDJ基因。基于主成分分析选择高度可变的基因,并基于肘部图(elbow plot)中的拐点选择成分数量。然后使用无监督的基于图形的聚类方法对细胞进行聚类,并绘制UMAP进行可视化。使用MAST进行差异基因表达分析,并使用上调基因来定义每个聚类。
scVDJ数据使用具有默认设置的cellranger pipeline进行类似处理。然后,将T细胞受体数据映射到基因表达数据上,以确定各个TCR克隆的转录组分布。K均值聚类基于TCR在转录组聚类中的分布对TCR进行聚类。
实施例3:克隆
为了克隆TCR,从Twist Biosciences获得TCR可变区的合成α和βVDJ片段。将TCR可变片段插入带有S/MAR序列的表达载体(pSMARTer)中,该载体实现使用单步Bsa-I介导的Golden Gate反应在真核细胞中进行染色体外复制。该表达载体被设计成含有鼠α和β恒定TCR区和p2a自切割肽接头,以促进TCR的单独α和β多肽链的产生。随后将载体转化至NEB5-α感受态大肠杆菌(NEB)中;通过抗生素抗性筛选转基因菌落;并使用NucleoBond ExtraMaxi EF试剂盒(Macherey-Nagel)制备的无内毒素质粒进行转染。
实施例4:NFAT测定
使用电穿孔(Neon转染系统,ThermoFisher Scientific)将克隆的TCR表达载体和基于纳米荧光素酶的NFAT报告载体(pDONR,具有4×NFAT响应元件)转染至JurkatΔ76细胞中。简言之,每次电穿孔利用Neon 100μl尖端(8μg TCR表达载体+5μg NFAT报告载体)使用2x106个细胞。根据生产商的方案收获并洗涤细胞,然后用1325V、10ms、3个脉冲进行电穿孔,并转移至含有10%FCS的不含抗生素的RPM1 1640培养基中。患者自体PBMC用作抗原呈递细胞(APC),解冻24h,然后在含有50U/ml Benzonase(Sigma-Aldrich)的X-VIVO 15培养基(Lonza)中共培养,并在以每孔1.5×105个细胞接种于96孔白色不透明组织培养处理板(Falcon)之前静息6-8h。将肽以终浓度10μg/ml、总体积150μl负载细胞16小时。使用的肽是等浓度的人IDH1R132H肽(p123-142)、MOG(p35-55)和等体积的PBS+10%DMSO(运载体)作为阴性对照。电穿孔后48h,收获TCR转基因JurkatΔ76细胞并与负载肽的PBMC以1:1的比例共培养6h。使用人T细胞TransAct珠(Miltenyi)作为阳性对照。使用公众已知的针对流感HA(p307-319)的TCR作为测定参考。根据生产商的方案,使用Nano-Glo荧光素酶测定系统(Promega)测定表明TCR活化的纳米荧光素酶诱导,并在PHERAstar FS酶标仪(BMGLabtech)上检测信号。
实施例5:基于FACS的测定
如上所述通过PCR添加T7启动子进行克隆。然后,使用DNA Clean&Concentrator-5(Zymo Research)纯化PCR产物,并根据生产商的方案使用Cellscript试剂盒用作体外转录的模板。分别通过Nanodrop和Bioanalyzer评估RNA的浓度和完整性。然后使用Lonza 4D核转染(nucleofactor)装置将RNA电穿孔至扩增的自体PBMC中。电穿孔后,细胞在室温下孵育10分钟,然后接种至含有1mL培养基(TexMACS+2%AB)的48孔板中,并静置过夜。孵育前,将150k细胞用CD3、CD4、CD8a、mTCRβ染色以用作对照。然后,将其余的电穿孔细胞与靶细胞(肿瘤细胞系/患者来源的异种移植物)共孵育5小时,1小时后添加Golgistop和Golgiplug。共孵育后,对细胞进行死细胞生物标志物CD3、CD4、CD8a、mTCRβ、TNFα和IFNγ染色,然后使用FACSLyric(BD Biosciences)进行测量。使用FlowJo进行分析。在图6B的示例性分析中,对细胞进行死细胞生物标志物CD3、CD4、CD8a、mTCRβ、TNFα和CD107a的染色,然后使用FACSLyric进行测量。
实施例6:结果-1
6.1基于基因表达的T细胞聚类
使用基于图的无监督聚类对单细胞RNA-seq数据集进行归一化、转换和聚类。此处显示了2名选定患者的数据。分别从患者1(图1A)和患者2(图1B)中鉴定出15个聚类和16个聚类。
6.2特征基因的表达
使用MAST进行差异基因表达,并发现每个聚类的上调基因表达。在多名患者中,我们鉴定出表达特征基因CCL3、CCL3L1、CCL4和CCL4L2的聚类。图1D-1F和图1G-1J显示了2名选定患者的特征基因的表达。在选定的患者中也显示另一个特征基因CXCL13的表达(图1K)。
6.3基于特征基因定义反应聚类
基于特征基因CCL3、CCL3L1、CCL4和CCL4L2的表达,定义反应聚类(图2A和2B)。基于特征基因CXCL13的表达定义的反应聚类如图2C所示。
6.4CCL3/CCL3L1/CCL4/CCL4L2特征
图3A描绘了患者1中频率最高的13个TCR克隆型。如前所述,表达特征基因的聚类4被定义为特征聚类。从分布中,我们可以清楚地看到TCR1、TCR12和TCR13在特征聚类中T细胞的分布较高。
图3B显示了基于特征聚类中T细胞分数的k均值聚类结果。根据该聚类结果发现了3个聚类。特征聚类中具有高分数的T细胞的聚类应该是反应性的,具有中等分数的T细胞的聚类应该是可能反应性的,而特征聚类中具有最低分数的T细胞的聚类应该是非反应性的。因此,TCR1被预测为有反应性,TCR12和TCR13被预测为可能有反应性,而其他TCR则无反应性。然后,克隆TCR以测试这些TCR的肿瘤反应性并证实基于特征基因的TCR预测。
图3C显示了基于FACS的TCR测试的结果。如特征基因所预测的,仅TCR1、TCR13和可能的TCR12在与相应患者的肿瘤细胞共培养时分泌IFNγ,从而表明TCR1和TCR13确实对癌细胞有反应,而TCR12可能有反应。
6.5CXCL13特征
图4A显示了患者2中频率最高的前5个CD4 TCR。从分布来看,很明显TCR4是唯一在特征聚类中具有较高分布的TCR。进一步的k均值聚类(图4B)还发现,在此特征聚类中存在2个基于T细胞分数的聚类。然后,预测仅由TCR4组成的具有较高分数的聚类具有反应性。然后克隆该TCR并使用NFAT测定进行测试。当与负载肽的PBMC共培养时,通过基因特征预测具有肿瘤反应性的TCR4确实具有反应性(图4C)。该TCR4的确切序列如SEQ ID NO:1和2所示。
实施例7:基于特征预测反应性TCR
来自单细胞分析的Seurat对象被转换成R中Monocle包中的“cell_data_set”对象。然后使用R中的Garnett包使用特征基因训练分类器。然后,将分类器鉴定的反应性T细胞映射到UMAP以鉴定反应性聚类。然后,使用R中的插入符包计算F评分(精确度和召回率的组合)。
实施例8:结果-2
8.1脑转移患者反应性TCR的预测
使用我们先前在患者1和患者2中鉴定的特征基因,我们在单独的患者(患者3)中证实了预测能力。从患者3的脑转移切除中提取浸润性CD 8+T细胞(TIL),并进行处理以生成scRNA和scVDJ文库,用于如前所述(实施例1)进行测序。使用UMAP图(一种降维方法)对所得数据进行处理和二维可视化(图6A),其中相似的细胞比不相似的细胞聚类得更紧密。图中的每个点代表一个细胞,每个细胞的基因表达谱和TCR均是已知的。证实了患者1和患者2的结果,核心基因在特定区域内共表达(图6H-L)。
使用基于FACS的测定测试从TIL克隆的许多TCR克隆型对肿瘤的反应性(如以上实施例5中所述)。然后可以将该反应性信息叠加到UMAP图上;很明显,表达肿瘤反应性TCR克隆型的TIL主要聚类在UMAP图上实线包围的区域内(图6A)。
我们继续阐明了对于预测给定T细胞克隆型是否具有肿瘤反应性(我们的TCR反应性“特征”)最重要的主要基因(实施例1)。特征的质量可以通过测定特征所识别的细胞中有多少表达已知对肿瘤有反应的TCR来通过计算来进行近似(通过将已知肿瘤反应性TCR的位置与UMAP图中的预测进行比较,可以以图形方式进行近似)。
我们说明了如何使用基于5个核心基因特征(图6B)、7个可选的核心基因特征(图6C)、核心和辅助基因特征(图6D)和特征2基因特征(图6E)的反应性预测将不同特征映射到UMAP图上。为了显示特征基因预测的稳健性,预测的非反应性TCR克隆型也被克隆并确认代表真正的非反应性TCR克隆型。
Lowery等人已报道反应性T细胞的两个特征,每个特征对表达CD4或CD8的T细胞特异(Science(2022,比较实施例A)和WO 2021/188954A1(比较实施例B))。这些特征的性能与本文公开的特征(表7)进行基准比较,并且本文公开的新特征被证明表现明显更好(即具有更高的F分数,即在预测表达肿瘤反应性TCR的细胞时具有更高的精确度和召回率)。
8.2神经胶质瘤患者反应性TCR的预测
从患有IDH1.R132H突变肿瘤的原发性神经胶质瘤患者的假性进展样品中提取浸润T细胞(TIL),并如前所述制备和测试单细胞文库。这些TCR源自CD4+ T细胞。
我们发现由Lowery等人开发的CD4+细胞特异性的基因特征(图7F、7G)在预测肿瘤反应性T细胞方面的表现并不比特征2基因特征更好。此外,我们发现,通过将我们的分析限制在不表达CD8B的细胞中,我们的基因特征比Lowery等人报道的特征要好得多(图7B)-E),表9)。这表明我们的基因特征对于不同肿瘤模式以及CD4+和CD8+细胞的肿瘤反应性具有普遍适用性。
8.3肺癌患者反应性TCR的预测
使用Caushi等人(2021)发表的肺癌数据集进一步验证了抗肿瘤反应性的特征,通过实验证实了肿瘤反应性TCR;我们将这些数据映射到相应的UMAP上,以显示TIL表达肿瘤反应性克隆型(图8A)。如先前在脑转移中所显示的,尽管我们的特征接受了脑癌样品的训练,但其表现始终优于Lowery等人开发的特征(图8B-8G,表8)。
9.实施例中使用的基因列表(特征)
9.1“5个核心基因”(“核心”):
CCL3L1、CCL4、CCL4L2、CCL3和CXCL13。
9.2“7个可选核心基因”(“核心-2”):
CCL3L1、LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B。
9.3发明的其他特征:
分别参见下表1至10的所有生物标志物。
9.4比较特征:
Lowery等人(2022)中使用的基因(CD8):
ATP10D、GZMB、ENTPD1、KIR2DL4、LAYN、HTRA1、CD70、CXCR6、HMOX1、ADGRG1、LRRN3、ACP5、CTSW、GALNT2、LINC01480、CARS、LAG3、TOX、PTPRCAP、ASB2、ITGB7、PTMS、CD8A、GPR68、NSMCE1、ABI3、SLC1A4、PLEKHF1、CD8B、LINC01871、CCL4、NKG7、CLIC3、NDFIP2、PLPP1、PCED1B、CXCL13、PDCD1、PRF1、HLA-DMA、GPR25、CD9、TIGIT、HLA-DRB5、SYTL3、SLF1、NEK1、CASP1、SMC4、TSEN54、PLSCR1、GNPTAB、HLA-DPB1、PLEKHA1、ARHGAP9、ALOX5AP、SH3BP1、NCF4、NELL2、GATA3、PPM1M、TNFRSF1A、AC022706.1、MCM5、HLA-DRB1、TNFSF10、TRIM21、HDLBP、ERN1、CALHM2、SASH3、ACTA2、MAST4、CAPG、MPST、IGFLR1、GZMA、CD27、ITGAE、SLA2、RHOC、COMMD8、MYO1G、SP140、PHPT1、CD2BP2、PLEKHO1、STAM、MRPL16、IL2RB、ID2、TESPA1、GOLGA8B、MIS18BP1、VAMP5、DAPK2、HLA-DPA1、TSG101、IL4R、CCND2、CTSC、TRAF3IP3、NLRC3、ORAI3、GNLY、MIR155HG、CARD16、CD82、ECH1、JAML、EEF1G、ETFB、DAXX、RBM4、HCST、RAB27A、YPEL2、CHST12、ARPC1B、PDIA4、PDIA6、AC243960.1、TBC1D10C、PTPN6、PYCARD、BST2、BTN3A2、MTG1、MLEC、DUSP4、GSDMD、SLAMF1、IFI6、PCID2、GIMAP1、ITGA1、CSNK2B、CDK2AP2、MYO1F、AC004687.1、PTTG1、APOBEC3C、TSPAN14、MOB3A、STXBP2、LCP2、PLA2G16、LINC00649、CST7、TADA3、SIT1、APOBEC3G、SUSD3、CD3G、CCL5、CDC25B、TNFRSF1B、HMGN3、THEMIS、ASF1A、CTNNB1、FIBP、CCDC85B、POLR3GL、GIMAP6、ARL6IP1、CALCOCO2、CCPG1、KLRB1、ACAA2、ISG15、EIF4A1、CAT、MANF、XAB2、GRINA、GLO1、LSM2、SLFN5、FKBP1A、AKNA、TAP1、LMO4、APEH、C12orf75、TMEM14A、DNPH1、C17orf49、NUDT5、MGAT1、CCDC69、EIF4EBP1、PDHB、ARL3、UCP2、IFI35、HSBP1、LYST、MRFAP1L1、ITGAL、AIP、RASAL3、CAPN1、ITGB1、RBPJ、LBH、DYNLL1、NME2、MT1F、SYNGR2、ABTB1、ZGPAT、CD63、ILK、SKA2、TMEM204、ACO2、HOPX、CRIP1、OXNAD1、CCS、GRAP2、GSTO1、HADHB、IL16、PIN4、CUEDC2、CALM3、SAMSN1、HM13、SNAP23、LPCAT4、FAAP20、EFHD2、PRDX3、CCM2、C22orf39、SDHA、ARRDC1、MAP4K1、NDUFA13、IL27RA和C14orf119。这些基因用于实施例8.1和8.3。
Lowery等人(2022)中使用的基因(CD4):
CXCL13、HMOX1、ETV7、ADGRG1、PDCD1、ENTPD1、CCDC50、TOX、CD4、TIGIT、TNFRSF18、NMB、MYL6B、AHI1、MAF、IFNG、LAG3、CXCR6、IGFLR1、DUSP4、ACP5、LINC01943、LIMS1、BATF、PCED1B、ITGAL、YPEL2、MAL、PPT1、ELMO1、MIS18BP1、TMEM173、ADI1、SLA、GALM、LBH、SECISBP2L、CTSB、C17orf49、CORO1B、CARHSP1、SRPK2、ARL3、PTMS、CD82、HNRNPLL、CTSC、LINC01871、CCDC167、SMC3、PPM1G、ORMDL3、VPS25、BST2、TRAF3IP3、NAP1L4、HLA-DPA1、PIM2、SH2D1A、RILPL2和CCNDBP1。这些基因用于实施例8.2。
WO 2021/188954 A1中使用的基因(CD8)
AFAP11L2、ASB2、CXCL13、HMOX1、ITM2A、KLRB1、PDLIM4、TIGIT、AFAP11L2、ALOX5AP、ARHGAP9、ASB2、CARD16、CD3G、CD8A、CD8B、CLIC3、CTSW、CXCL13、CXCR6、GALNT2、GZMB、HLA-PDA1、HLA-DPB1、HLA-DRB1、HLA-DRB5、HMGN3、HMOX1、ITGAE、ITM2A、KLRB1、MPST、NAP1L4、NELL2、NSMCE1、PDLIM4、PTMS、RAB27A、RARRES3、RBPJ、TIGIT、CD39、CD74、CD103、CD106、CD137、HLA-DR、TIGIT、ABI3、AC243960.1、ACP5、ADGRG1、AHI1、ASB2、BST2、CARS、CCL4、CD27、CD2BP2、CD82、CTSW、CXCL13、CXCR6、DUSP4、ENTPD1、GALNT2、GATA3、GPR25、GZMB、HDLBP、HLA-DPA1、HLA-DRB1、HMOX1、ID2、IGFLR1、LINC01871、LINC01943、MIS18BP1、MPST、NCF4、NSMCE1、PCED1B、PDCD1、PHPT1、PLEKHF1、PRF1、PTMS、SLC1A4、SLF1、SMC4、SUPT3H、TIGIT、TNFRSF18、TOX、TRAF3IP3、YPEL2、AC243829.4、ACP5、APOBEC3C、APOBEC3G、CCL3、CCL4、CCL4L2、CCL5、CD27、CD8A、CD8B、CST7、CTSW、CXCL13、DUSP4、ENTPD1、FABP5、GALNT2、GNLY、GZMA、GZMB、GZMH、GZMK、HAVCR2、HCST、HLA-DMA、HLA-DPA1、HLA-DPB1、HLA-DRA、HLA-DRB1、HLA-DRB5、HMOX1、IFNG、IGFLR1、ITGAL、JAML、LINC01871、LYST、MIR155HG、NKG7、PLEKHF1、PRF1、PTMS、RGS1、SLF1、SMC4、SUPT3H、TIGIT、TOX、AHI1、CXCL13、FABP5、NAP1L4、ORMDL3、PPP1R116B、SH2D1A、TIGIT、TOX、TIGIT、CD39、PD-1、LTB、LYAR、RGCC、S100A10、CD39、CD74、CD103、CD106、CD137、HLA-DR、TIGIT、CCR7、CD8A、CD16、CD45RA、CD62L和IL7R。这些基因用于实施例8.1和8.3。
WO 2021/188954 A1中使用的基因(CD4)
AFAP11L2、ASB2、CXCL13、HMOX1、ITM2A、KLRB1、PDLIM4、TIGIT、BATF、CD247、DNPH1、DUSP4、GYPC、IFITM1、IGFLR1、LIMS1、NMB、NR3C1、SH2D1A、SPOCK2、SUPT3H、TNFRSF18、ADI1、AHI1、AR1D5B、CMTM7、CPM、CYTH1、ELMO1、ETV7、FABP5、FBLN7、FKBP5、GRAMD1A、HIF1A、IL6ST、ITGA4、ITK、JAK3、LEF1、MAF、MAL、MIR4435-2HG、MYL6B、NAP1L4、PASK、PGM2L1、PIM2、PPP1CC、SESN3、SOCS1、STAT1、SYNE2、TBC1D4、TLK1、TMEM123、TMEM70、TNIK、TOX、TSHZ2、UCP2、VOPP1、YPEL2、ABI3、AC243960.1、ACP5、ADGRG1、BST2、CARS、CCL4、CD27、CD2BP2、CD82、CTSW、CXCR6、ENTPD1、GALNT2、GATA3、GPR25、GZMB、HDLBP、HLA-DPA1、HLA-DRB1、ID2、LINC01871、LINC01943、MIS18BP1、MPST、NCF4、NSMCE1、PCED1B、PDCD1、PHPT1、PLEKHF1、PRF1、PTMS、SLC1A4、SLF1、SMC4、TRAF3IP3、ORMDL3、PPP1R116B、CD39、PD-1、LTB、LYAR、RGCC、S100A10、CCL5、CD52、GSTSP1、JUN、LGALS1、PLP2、VIM和ZFP36。这些基因用于实施例8.2。
引用的参考文献:
Caushi等人(2021),Nature 596(7870):126
Cano-Gamez等人(2020),Nat Comm 11:,art.1801(doi.org/10.1038/s41467-020-15543-y)
Iwabuchi&van Kaer(2019),Front Immunol 10:1837(doi:10.3389/fimmu.2019.01837)
Lowery等人(2022),Science 10.1126/science.abl5447
Magen等人(2019),Cell Rep 29(10):3019(doi.org/10.1016/j.celrep.2019.10.131)
MacQueen(1967),"Some methods for classification and analysis ofmultivariate observations",5th Berkeley Symposium on Mathematical Statisticsand Probability
McInnes等人(2020),arXiv:1802.03426v3
Oh等人(2020),Cell 181(7):1612(doi.org/10.1016/j.cell.2020.05.017)
van der Maaten and Hinton(2008),J Machine Learning Res 9:2579
WO2018/209324
WO2019/070755
WO 2021/188954 A1
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序列表
<110> 德国癌症研究中心
海德堡大学
<120> 抗原反应性T细胞受体
<130> DK16297PC
<150> EP21164371.3
<151> 2021-03-23
<160> 4
<170> PatentIn 3.5版
<210> 1
<211> 268
<212> PRT
<213> 智人
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Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val
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Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys
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Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His
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Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly
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Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
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290 295 300
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<210> 3
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cactccacaa tcagtggaac tgattacata cattggtatc gacagcttcc ctcccagggt 180
ccagagtacg tgattcatgg tcttacaagc aatgtgaaca acagaatggc ctctctggca 240
atcgctgaag acagaaagtc cagtaccttg atcctgcacc gtgctacctt gagagatgct 300
gctgtgtact actgcatcct gagagtcgca tactctgggg ctgggagtta ccaactcact 360
ttcgggaagg ggaccaaact ctcggtcata ccaaacatcc agaatcctga gcctgccgtg 420
taccagctga aggaccctag aagccaggac agcaccctgt gcctgttcac cgacttcgac 480
agccagatca acgtgcccaa gaccatggaa agcggcacct tcatcaccga caagtgtgtg 540
ctggacatga aggccatgga cagcaagagc aacggcgcca ttgcctggtc caaccagacc 600
agcttcacat gccaggacat cttcaaagag acaaacgcca cctatcctag cagcgacgtg 660
ccctgtgatg ccacactgac cgagaagtcc ttcgagacag acatgaacct gaacttccag 720
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gccccaaagc tgctgttcca ctactatgac aaagatttta acaatgaagc agacacccct 240
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ggcctggggg acgcagccat gtacctgtgt gccaccagca gaggagtggc agggagtagc 360
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gtgacccctc ctaaggtgtc cctgttcgag cctagcaagg ccgagatcgc caacaagcag 480
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tgggtcaacg gcaaagaggt gcacagcggc gtctgcacag atccccaggc ctacaaagag 600
agcaactaca gctactgcct gagcagcaga ctgagagtgt ccgccacctt ctggcacaac 660
cccagaaacc acttcagatg ccaggtgcag tttcacggcc tgagcgaaga ggacaagtgg 720
cctgagggct ctcccaagcc tgtgacacag aatatctctg ccgaagcctg gggcagagcc 780
gattgtggaa ttaccagcgc cagctaccag cagggcgtgc tgtctgccac aatcctgtac 840
gagatcctgc tgggcaaagc cactctgtac gccgtgctgg tgtctaccct ggtcgtgatg 900
gccatggtca agcggaagaa cagccggaag agaagaggaa gcggc 945
Claims (19)
1.一种鉴定对呈递T细胞活化抗原的受试者的细胞有反应的T细胞(反应性T细胞)的方法,其包括
(a)测定来自所述受试者的样品的T细胞中CCL3L1、CCL4、CCL4L2、CCL3和CXCL13中的至少一种的表达;和
(b)基于步骤(a)的测定,鉴定反应性T细胞,
优选地,其中所述T细胞活化抗原是癌症抗原或自身免疫T细胞活化抗原,更优选是癌症抗原。
2.根据权利要求1所述的方法,其中步骤(a)包括测定CCL3L1、CCL4、CCL4L2、CCL3和CXCL13中的至少两种、优选至少三种、更优选至少四种的表达。
3.根据权利要求1或2所述的方法,其中步骤(a)进一步包括测定选自由以下组成的列表的至少一种生物标志物的表达:IFNG、HAVCR2、FNBP1、CSRNP1、SPRY1、RHOH、FOXN2、HIF1A、TOB1、RILPL2、CD8B、GABARAPL1、TNFSF14、EGR1、EGR2、TAGAP、TNFSF9、ANXA1、MAP3K8、PIK3R1、DUSP2、DUSP4、DUSP6、CLIC3、RASGEF1B、LAG3、XCL2、NR4A2、DNAJB6、NFKBID、MCL1、EVI2A、SLC7A5、H3F3B、NR4A3、REL、IRF4、CST7、ATF3、TNF、GPR171、BCL2A1、ITGA1、TNFAIP3、NR4A1、RUNX3、HERPUD2、FASLG、CBLB、PTGER4、SLA、XCL1、BHLHE40、LYST、KLRD1、ZNF682、CTSW、SLC2A3、NLRP3、SCML4、VSIR、LINC01871和ZFP36L1。
4.根据权利要求1至3中任一项所述的方法,其中步骤(a)进一步包括测定选自由LAG3、GABARAPL1、CBLB、SLA、KLRD1和CLEC2B组成的列表中的至少一种生物标志物的表达,优选地包括测定权利要求1和/或权利要求4所述的所有生物标志物。
5.根据权利要求1至4中任一项所述的方法,其中步骤(a)进一步包括测定选自由以下组成的列表的至少一种生物标志物的表达:CTSD、CD7、CD3D、LSP1、SNAP47、GAPDH、KLRK1、TNS3、VCAM1、KLRC2、PMAIP1、FYN、CTLA4、GSTP1、AREG、FAM3C、SH3BGRL3、CD3E、SRGAP3、SRGN、SIRPG、SCPEP1、RHOB、ANKRD28、LINC02446、RABAC1、IKZF3、BCAS4、CD2、BLOC1S1、RHOA、EID1、MYL6、CLIC1、IQGAP1、ARPC2、PHYKPL、PRDM1、EVL、TPI1、ADGRE5、PAXX、RGS2、HERPUD1、IFI27L2、SEPTIN7、UBB、JUN、CFLAR、LITAF、ANXA5、STAT3、RSRP1、PRDX5、SEM1、SERPINB1、RNF19A、IL2RG、ENSA、SRP14、ATP6V0C、LY6E、BIN1、AKAP13、PDE4D、PELI1、PARK7、MSN、SERTAD1、RAC2、SELENOH、PSMB8、CKLF、KLRC1、RNASEK、MT2A、TXNIP和FOXP3。
6.根据权利要求1至5中任一项所述的方法,其中步骤(a)包括测定至少以下的表达:CCL3L1+CCL3;CCL3L1+CCL3+LAG3+KLRD1;CCL3L1+CCL3+CXCL13;CCL3L1+CCL3+CXCL13+KLRD1;CCL3L1+CCL3+CXCL13+LAG3;CCL3L1+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL3+KLRD1;CCL3L1+CCL3+LAG3;CCL3L1+CCL4+CCL3;CCL3L1+CCL4+CCL3+CXCL13;CCL3L1+CCL4+CCL3+CXCL13+KLRD1;CCL3L1+CCL4+CCL3+CXCL13+LAG3;CCL3L1+CCL4+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL3+LAG3;CCL3L1+CCL4+CCL3+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+LAG3;CCL3L1+CCL4+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+CCL3+KLRD1;CCL3L1+CCL4+CCL4L2+CXCL13;CCL3L1+CCL4+CCL4L2+CXCL13+KLRD1;CCL3L1+CCL4+CCL4L2+CXCL13+LAG3;CCL3L1+CCL4+CCL4L2+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+CCL4L2+LAG3+KLRD1;CCL3L1+CCL4+CXCL13;CCL3L1+CCL4+CXCL13+KLRD1;CCL3L1+CCL4+CXCL13+LAG3;CCL3L1+CCL4+CXCL13+LAG3+KLRD1;CCL3L1+CCL4+KLRD1;CCL3L1+CCL4+LAG3+KLRD1;CCL3L1+CCL4L2+CCL3;CCL3L1+CCL4L2+CCL3+CXCL13;CCL3L1+CCL4L2+CCL3+CXCL13+KLRD1;CCL3L1+CCL4L2+CCL3+CXCL13+LAG3;CCL3L1+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL3L1+CCL4L2+CCL3+KLRD1;CCL3L1+CCL4L2+CCL3+LAG3+KLRD1;CCL3L1+CCL4L2+CXCL13;CCL3L1+CCL4L2+CXCL13+KLRD1;CCL3L1+CCL4L2+CXCL13+LAG3;CCL3L1+CCL4L2+CXCL13+LAG3+KLRD1;CCL3L1+CCL4L2+KLRD1;CCL3L1+CCL4L2+LAG3;CCL3L1+CCL4L2+LAG3+KLRD1;CCL3L1+CXCL13;CCL3L1+CXCL13+KLRD1;CCL3L1+CXCL13+LAG3;CCL3L1+CXCL13+LAG3+KLRD1;CCL3L1+LAG3+KLRD1;CCL3+CXCL13;CCL3+CXCL13+KLRD1;CCL3+CXCL13+LAG3;CCL3+CXCL13+LAG3+KLRD1;CCL3+LAG3+KLRD1;CCL4+CCL3;CCL4+CCL3+CXCL13;CCL4+CCL3+CXCL13+KLRD1;CCL4+CCL3+CXCL13+LAG3;CCL4+CCL3+CXCL13+LAG3+KLRD1;CCL4+CCL3+KLRD1;CCL4+CCL3+LAG3+KLRD1;CCL4+CCL4L2+CCL3+CXCL!3;CCL4+CCL4L2+CCL3+CXCL13+KLRD1;CCL4+CCL4L2+CCL3+CXCL13+LAG3;CCL4+CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL4+CCL4L2+CCL3+KLRD1;CCL4+CCL4L2+CCL3+LAG3;CCL4+CCL4L2+CXCL13;CCL4+CCL4L2+CXCL13+KLRD1;CCL4+CCL4L2+CXCL13+LAG3;CCL4+CCL4L2+CXCL13+LAG3+KLRD1;CCL4+CCL4L2+KLRD1;CCL4+CCL4L2+LAG3+KLRD1;CCL4+CXCL13;CCL4+CXCL13+KLRD1;CCL4+CXCL13+LAG3;CCL4+CXCL13+LAG3+KLRD1;CCL4+LAG3+KLRD1;CCL4L2+CCL3;CCL4L2+CCL3+CXCL13;CCL4L2+CCL3+CXCL13+KLRD1;CCL4L2+CCL3+CXCL13+LAG3;CCL4L2+CCL3+CXCL13+LAG3+KLRD1;CCL4L2+CCL3+KLRD1;CCL4L2+CCL3+LAG3+KLRD1;CCL4L2+CXCL13;CCL4L2+CXCL13+KLRD1;CCL4L2+CXCL13+LAG3;CCL4L2+CXCL13+LAG3+KLRD1;CCL4L2+LAG3+KLRD1;CXCL13+LAG3;CXCL13+LAG3+KLRD1;KLRD1;KLRD1+CCL3;KLRD1+CCL3L1;KLRD1+CCL4L2;KLRD1+CXCL13;KLRD1+LAG3;表1的所有生物标志物;表5的所有生物标志物;或表6的所有生物标志物。
7.根据权利要求1至6中任一项所述的方法,其中所述T细胞活化抗原是癌症抗原,并且其中优选地所述样品是肿瘤样品。
8.根据权利要求7所述的方法,其中所述癌症是非脑原发性肿瘤的脑转移、是肺癌或是成胶质细胞瘤,优选地是非脑原发性肿瘤的脑转移或是肺癌。
9.一种鉴定与受试者的细胞、优选癌细胞上呈递的T细胞活化抗原结合的TCR的方法,所述方法包括
(A)根据权利要求1至4中任一项所述的方法鉴定反应性T细胞,
(B)提供步骤(A)中鉴定的反应性T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;并且,据此,
(C)鉴定与细胞上呈递的活化抗原结合的TCR。
10.根据权利要求1至9中任一项所述的方法,其中步骤a)的至少一种生物标志物的表达和/或编码步骤(B)的氨基酸序列的核酸序列通过单细胞测序、优选地通过单细胞RNA测序来测定。
11.根据权利要求9或10所述的方法,其中所述方法进一步包括步骤B1),其在宿主细胞、优选T细胞中表达至少包含步骤B)中测定的CDR的TCR。
12.根据权利要求11所述的方法,其中所述方法进一步包括步骤B2),其优选地在四聚体测定中,测定步骤B1)中表达的TCR与T细胞活化抗原的结合,所述T细胞活化抗原优选地在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。
13.根据权利要求11或12所述的方法,其中所述方法进一步包括步骤B3),其测定步骤B1)中表达的TCR对呈递T细胞活化抗原的细胞的识别。
14.根据权利要求9至13中任一项所述的方法,其中所述方法进一步包括步骤B4),其产生至少包含步骤B)中测定的CDR的可溶性TCR,并且测定所述可溶性TCR与癌细胞和/或与癌症抗原的结合,所述癌症抗原在主要组织相容性复合体(MHC)、优选MHC I类分子中复合。
15.一种提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞的方法,所述方法包括
(i)根据权利要求9至12中任一项所述的方法鉴定与呈递T细胞活化抗原的细胞结合的TCR,
(ii)在T细胞中表达至少包含步骤(I)的TCR的互补决定区(CDR)的TCR,并且,由此,
(iii)提供识别呈递T细胞活化抗原的细胞、优选癌细胞的T细胞。
16.通过根据权利要求1至8中任一项所述的方法鉴定的和/或通过根据权利要求9至14中任一项所述的方法获得的或可获得的反应性T细胞,其用于医学或用于治疗和/或预防受试者的癌症,所述反应性T细胞优选地包含T细胞受体,所述T细胞受体包含SEQ ID NO:1和/或SEQ ID NO:2的氨基酸序列。
17.一种鉴定反应性T细胞的至少一种生物标志物的方法,其包括
(I)提供受试者的样品中T细胞的多种生物标志物的表达数据,
(II)基于步骤(I)的生物标志物的表达,提供对所述多个T细胞的聚类;
(III)提供步骤(II)的T细胞的TCR的至少互补决定区(CDR)的氨基酸序列;
(IV)测定表达包含步骤(III)的CDR的TCR的T细胞对呈递T细胞活化抗原的细胞的反应性;
(V)针对另外的T细胞重复步骤(III)和(IV)至少一次,所述另外的T细胞与步骤(IV)中测定的TCR对呈递T细胞活化抗原的细胞有反应的T细胞聚类,其中所述另外的T细胞的TCR与步骤(IV)的TCR不相同;
(VI)确定步骤(II)的至少一个聚类,其包含最高分数的T细胞,所述T细胞包含识别呈递T细胞活化抗原的细胞的T细胞受体;和
(VII)测定由步骤(VI)中测定的聚类中最高分数的T细胞表达的至少一种生物标志物,从而鉴定癌症反应性T细胞的至少一种生物标志物。
18.根据权利要求1至17中任一项所述的主题,其中所述T细胞或多个T细胞是CD8+T细胞或CD4+T细胞,优选地是CD8+T细胞。
19.根据权利要求9至18中任一项所述的主题,其中所述TCR包含TCRα链和TCRβ链,优选地由TCRα链和TCRβ链组成。
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