CN112703039A - 用于调节调节性t细胞和抑制肿瘤生长的方法 - Google Patents
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Abstract
本公开描述了特异性地调节受试者中肿瘤内调节性T(Treg)细胞的活性和/或数量的方法。此类方法可用于降低受试者中肿瘤内调节性T细胞的数量,以及抑制患有癌症的受试者中肿瘤生长而不引发自身免疫反应。此方法依赖于对CD36或PPARbeta的抑制。
Description
相关申请的交叉引用
根据35 U.S.C.§119(e),本申请要求于2018年9月14日提交的美国临时专利申请号62/731,351的优先权。前述申请的全部内容通过引用并入本文。
发明领域
本发明涉及在受试者中调节肿瘤内调节性T(Treg)细胞并抑制肿瘤生长的方法,更具体地涉及通过CD36抑制剂或PPARβ抑制剂在受试者中调节肿瘤内Treg细胞并抑制肿瘤生长的方法。
发明背景
调节性T(Treg)细胞是独特的T细胞群体,其调节免疫系统,维持对自身抗原的耐受,抑制自身反应性T细胞的异常激活以及消除自身免疫疾病。Treg细胞通过多种机制介导其调节功能。首先,Treg细胞表达抗炎细胞因子,其包括IL-10、TGFβ和IL-35。调节的另一种机制是通过细胞间接触。Treg细胞上表达的细胞毒性T淋巴细胞抗原4(CTLA-4)以比CD28高约10倍的亲和力与抗原呈递细胞(APC)上的共刺激B7分子结合,从而阻止APC激活幼稚T细胞。还提出了Treg细胞通过消耗T细胞激活和极化所需的细胞因子(例如IL-2、IL-4、IL-7)来预防效应T细胞分化(Ward-Hartstonge和Kemp.Clinical&TranslationalImmunology,6:9(2017))。
使用的癌细胞逃避免疫监视的一种机制是诱导Treg细胞,进而抑制生物体的天然免疫应答。预期通过使Treg细胞失活,可以避免免疫系统的抑制,并且免疫系统将能够发起(mount)响应以破坏原发性和转移性肿瘤。已经显示,消减Treg细胞释放抗肿瘤免疫力并中断免疫抑制肿瘤微环境(TME)的形成。然而,由于Treg消减而导致的Treg细胞的系统性损失通常会导致严重的自身免疫(Wang,H.,et al.Trends Cancer 3,583-592(2017))。
在小鼠和人类癌症中均以高频率发现Treg(Roychoudhuri,R.,Eil,R.L.&Restifo,N.P.The interplay of effector and regulatory T cells incancer.Current opinion in immunology 33,101-111(2015);Delgoffe,G.M.etal.Nature 501,252-256(2013);Saito,T.et al.Nat Med 22,679-684(2016)),它们代表了抗肿瘤免疫和癌症免疫疗法的主要障碍(Rech,A.J.et al.Sci Transl Med 4,134ra162(2012);Sutmuller,R.P.et al.J Exp Med 194,823-832(2001))。尽管消减Treg的策略会增加抗肿瘤响应,但由于Treg的系统性损失和效应T细胞的不必要消减所引起的严重自身免疫,限制了Treg靶向方法的治疗潜力。此外,靶向在Treg中表达的免疫检查点(例如OX40、GITR和CTLA-4)的治疗对Treg中抑制功能的系统性损害也阻碍了Treg靶向方法在癌症治疗中的应用(Nishikawa,H.&Sakaguchi,S.International journal of cancer 127,759-767(2010);Simpson,T.R.et al.J Exp Med 210,1695-1710(2013);Curtin,J.F.et al.PLoSOne 3,e1983(2008))。迄今为止,寻找选择性地破坏肿瘤内Treg的有效的靶向方法仍然是癌症免疫疗法的挑战。
因此,仍然迫切需要一种特异性靶向肿瘤内Treg细胞以诱导抗肿瘤免疫而不引起自身免疫应答的方法。
发明概述
本公开描述了降低受试者中肿瘤内Treg细胞数量的方法和增加受试者中肿瘤内细胞毒性T细胞数量的方法。该方法可用于抑制患有癌症的受试者中的肿瘤生长。
在一方面,本公开提供了降低受试者中肿瘤内Treg细胞(例如,CD4+细胞)数量的方法。该方法可以包括向所述受试者施用有效量的CD36抑制剂。在一些实施方案中,该方法可以包括向所述受试者施用有效量的PPARβ抑制剂。
在第二方面,本公开提供了增加受试者中肿瘤内细胞毒性T细胞(例如,CD8+细胞)的数量的方法。该方法可以包括向所述受试者施用有效量的CD36抑制剂。在一些实施方案中,该方法可以包括向所述受试者施用有效量的PPARβ抑制剂。
CD36抑制剂可以是抗CD36抗体或小分子CD36抑制剂。抗CD36抗体可以是人抗体、人源化抗体、嵌合抗体或双特异性抗体。小分子CD36抑制剂的非限制性实例可包括AP-5258、AP5055、EP-80317、MPE-002、CHEML1789142、CHEML1789302、CHEML1789297、CHEML1789141、CHEML1789270、CHEML1789308。类似地,PPARβ抑制剂可以是抗PPARβ抗体或小分子PPARβ抑制剂。小分子PPARβ抑制剂的实例可包括但不限于FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
在一些实施方案中,降低受试者中肿瘤内Treg细胞数量的方法可以进一步包括向所述受试者施用额外的治疗剂。所述额外的治疗剂可以是免疫检查点调控剂,例如对以下具有特异性的抗体:CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。
CD36抑制剂、PPARβ抑制剂或额外的治疗剂可以以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
在一些实施方案中,受试者可以患有癌症。癌症的非限制性实例可包括口腔癌、口咽癌、鼻咽癌、呼吸道癌、泌尿生殖道癌、胃肠道癌、中枢或周围神经系统组织癌、内分泌或神经内分泌癌或造血癌、神经胶质瘤、肉瘤、癌瘤(carcinoma)、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺瘤、成骨肉瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头和颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌和皮肤癌。
在第三方面,本公开提供了在患有癌症的受试者中抑制肿瘤生长的方法。该方法可以包括向所述受试者单独或与额外的治疗剂组合施用治疗有效量的CD36抑制剂。在一些实施方案中,该方法可以包括向所述受试者单独或与额外的治疗剂组合施用治疗有效量的PPARβ抑制剂。
CD36抑制剂可以是抗CD36抗体或小分子CD36抑制剂。CD36抑制剂可以是抗CD36抗体或小分子CD36抑制剂。抗CD36抗体可以是人抗体、人源化抗体、嵌合抗体或双特异性抗体。小分子CD36抑制剂的非限制性实例可包括AP-5258、AP5055、EP-80317、MPE-002、CHEML1789142、CHEML1789302、CHEML1789297、CHEML1789141、CHEML1789270、CHEML1789308。类似地,PPARβ抑制剂可以是抗PPARβ抗体或小分子PPARβ抑制剂。小分子PPARβ抑制剂的实例可包括但不限于FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
额外的治疗剂可以是免疫检查点调控剂,例如对免疫检查点特异性的抗体。免疫检查点的实例可包括CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。在一些实施方案中,额外的治疗剂包括PD-1抑制剂。在一些实施方案中,额外的治疗剂包括CTLA-4抑制剂。在一些实施方案中,额外的治疗剂包括PD-1抑制剂和CTLA-4抑制剂二者。
CD36抑制剂、PPARβ抑制剂或额外的治疗剂可以以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
前述概述并非旨在定义本公开的每个方面,并且其他方面在诸如以下详细描述的其他部分中进行了描述。整个文档旨在作为一个统一的公开内容进行关联,并且应该理解,即使在本文档的同一句子或段落或部分中未发现的特征的组合,也可以预期本文描述的特征的所有组合。通过以下详细描述,本发明的其他特征和优点将变得显而易见。然而,应当理解,尽管详细描述和具体实例指示了本公开的具体实施方案,但它们仅以说明的方式给出,因为根据该详细描述,在本公开的精神和范围内的各种改变和修改对于本领域技术人员将变得显而易见。
附图简述
图1a、1b、1c、1d、1e和1f是显示肿瘤内Treg提高了CD36以及参与脂质代谢的基因的表达的一组图。图1a显示了途径富集分析,重点针对来自乳腺癌和乳腺癌患者的PBMC的Treg中RNA表达的代谢机制。提出了在肿瘤内和PBMC Treg之间具有显著差异表达的途径(P<0.05)。图1b显示了通过基因集富集分析(GSEA)鉴定的,与PBMC Treg相比,肿瘤内Treg中的脂肪酸代谢过程(上图)和脂质结合(下图)途径的富集图。热图显示每个标签基因的表达水平。柱表示单个样品,行是每个基因。指示了高表达水平和低表达水平。图1c和1d显示了来自荷Yumm1.7黑色素瘤B6小鼠所示组织的Treg中Bodipy FL C12(图1c)和Bodipy 493/503(图1d)的代表性直方图(左)和几何平均值(GeoMean)荧光强度(右)的定量结果。DLN:引流淋巴结(n≥5);LN:非引流淋巴结(n=5);脾脏(n≥5);胸腺(n=5);肿瘤(n≥5)。图1e和1f显示了来自黑色素瘤患者的PBMC和TIL(n=12)(图1e)和来自荷Yumm1.7黑色素瘤B6小鼠(DLN,n=15;脾脏,n=15;胸腺,n=9;肿瘤,n=14)(图1f)所示组织的Treg中CD36表面染色的代表性直方图(左)和几何平均值(GeoMean)荧光强度的定量结果。TIL:肿瘤浸润淋巴细胞。数据是三个独立实验的代表性结果(图1c和1d)或来自三个独立实验的累积结果(图1e和1f)。每个符号代表一个个体。数据为平均值±S.D.,且通过双尾未配对的学生t检验进行分析。**P<0.01,***P<0.001。
图2a、2b、2c、2d、2e、2f、2g、2h、2i和2j是显示CD36的破坏选择性地损害了肿瘤内Treg的积累和抑制功能的一组图。图2a显示了21-23周龄时来自WT或TregCD36-/-小鼠的所示组织的苏木精和曙红(H&E)染色的代表性图像。比例尺,200μm。图2b和2c显示了来自荷Yumm1.7黑色素瘤WT或TregCD36-/-小鼠(每组n=6)的脾脏和肿瘤内Treg中Bodipy FL C12(图2b)和Bodipy 493/503(图2c)的代表性直方图(左)和几何平均值(GeoMean)荧光强度(右)的定量结果。图2d和2e显示了来自野生型(WT)或TregCD36-/-小鼠(WT,n>9;TregCD36-/-,n>13)的YUMM1.7黑色素瘤的肿瘤生长(图2d)和肿瘤重量(图2e)。Foxp3YFP-Cre小鼠用作WT小鼠。图2f显示了在荷瘤WT和TregCD36-/-小鼠的所示组织中(脾脏,n>12;LN,n>11;肿瘤,n>13)的CD4+T细胞中FoxP3+ Treg的代表性图(左)和百分比。图2g显示了代表性的图(左)和在来自所示小鼠的总的肿瘤浸润CD8+T细胞中所示的产生细胞因子的CD8+T细胞的百分比(右)(每组n=5)。图2h和2i显示了从肿瘤(图2h)或脾脏(图2i)分选的WT和TregCD36-/-Treg以注释的比例离体抑制CFSE标记的WT幼稚CD8+T细胞的增殖。图2j显示了Rag1-/-小鼠接受单独的幼稚CD4+T细胞或幼稚CD4+T细胞与WT或TregCD36-/-Treg组合的体重测量(媒介物,n=4;幼稚CD4,n=7;WT Treg,n=6;TregCD36-/-,n=6)。数据是至少两个独立实验的代表结果(图2b、2c和2g)或三个独立实验的累积结果(图2d、2e、2f、2h、2i和2j)。每个符号代表一个个体。数据为平均值±S.D.(图2b、2c、2e、2f、2g、2h和i)或±S.E.M.(图2d和2j),并通过双尾未配对的学生t检验(图2b、2c、2d、2e、2f、2g、2h和2i)或单因素方差分析与Tukey多重比较检验(图2j)进行分析。*P<0.05,**P<0.01,***P<0.001,****P<0.0001,ns,无显著性差异。
图3a、3b、3c、3d、3e、3f、3g、3h和3i是显示CD36缺乏刺激肿瘤内Treg的凋亡的一组图。图3a显示了通过RNA-seq评估的WT和TregCD36-/-肿瘤内Treg中与凋亡途径相关的基因的表达(每组n=3)。具有P值<0.05表明差异表达的基因。图3b显示了来自WT(n=13)和TregCD36-/-荷瘤小鼠(n=14)的肿瘤内Treg中切割的胱天蛋白酶-3水平的代表性直方图(左)和定量分析(右)。图3c显示了来自荷瘤WT和TregCD36-/-小鼠(每组n>8)的脾脏、非引流淋巴结(LN)、引流淋巴结(DLN)、血液、胸腺和肿瘤的Treg中的MitoTracker Deep Red(MDR)染色的代表性直方图(左)和定量分析(右)。图3d和3e显示了来自荷瘤WT和TregCD36-/-小鼠脾脏和肿瘤内Treg中线粒体数量(图3d)和嵴密度(图3e)的代表性电子显微镜图像(左)和定量图(右)。在(图3d)中比例尺:500nm和在(图3e)中比例尺:200nm。图3f显示了在癌细胞条件培养基中培养48小时的指示iTreg的OCR(每组n≥4)。图3g显示了如上在癌细胞条件培养基中培养的WT或TregCD36-/-iTreg的生存力,然后用所示浓度的乳酸处理另外72小时(每组n≥4)。图3h显示了在癌细胞条件培养基中培养48小时所示的iTreg的NAD/NADH比率(WT,n=11;TregCD36-/-,n=13)。图3i显示了用具有或不具有NR(400μM)的癌细胞条件培养基处理72小时的WT或TregCD36-/-iTreg的相对生存力(每组n=11)。将结果标准化为所示组中对照处理的存活细胞。NR:烟酰胺核糖。数据是三个独立实验的代表结果(图3f和3g)或三个独立实验的累积结果(图3b、3c、3h和3i)。数据为平均值±S.D.且通过双尾未配对的学生t检验进行分析。*P<0.05,**P<0.01,***P<0.001,****P<0.0001,ns,无显著性差异。
图4a、4b、4c、4d、4e、4f、4g、4h和4i是显示PPARβ信号转导是肿瘤内Treg代谢适应所必需的一组图。图4a显示了通过基因集富集分析(GSEA)鉴定的与PBMC Treg相比,肿瘤内Treg中的PPAR信号转导途径的富集图。热图显示每个标签基因的表达水平。图4b显示了来自荷瘤WT和TregPPARβ-/-小鼠的CD4+肿瘤浸润T淋巴细胞中FoxP3+Treg的百分比。图4c和4d显示来自野生型(WT)或TregPPARβ-/-小鼠(WT,n=15;TregCD36-/-,n=10)的YUMM1.7黑色素瘤的肿瘤生长(图4c)和肿瘤重量(图4d)。Foxp3YFP-Cre小鼠用作WT小鼠。图4e显示来自WT和TregPPARβ-/-小鼠的肿瘤内Treg中MDR染色的几何MFI的定量结果(每组n=5)。图4f和4g显示WT和TregCD36-/-小鼠被植入YUMM1.7黑色素瘤细胞,然后如方法中所述用DMSO或PPARβ激动剂处理。分析了肿瘤生长(图4f)(WT+DMSO,n=6;TregCD36-/-+DMSO,n=11;WT+PPARβ激动剂,n=5;TregCD36-/-+PPARβ激动剂,n=9)和CD4+肿瘤浸润T淋巴细胞中FoxP3+Treg的百分比(图4g)(每组n≥9)。图4h和4i显示了用所示治疗处理的WT和TregCD36-/-小鼠肿瘤内Treg中的MitoTracker Deep Red(MDR)染色(图4h)和切割的胱天蛋白酶-3的表达(图4i)的定量分析(每组n≥9)。数据是三个独立实验的代表结果(图4b和4e)或至少三个独立实验的累积结果(图4c、4d、4f、4g、4h和4i)。数据为平均值±S.D.(图4b、4d、4e、4g、4h和4i)或±S.E.M.(图4c和4f),并通过双尾未配对的学生t检验进行分析。*P<0.05,**P<0.01,***P<0.001,ns,无显著性差异。
图5a、5b、5c、5d、5e、5f、5g和5h是显示靶向CD36的受损肿瘤内Treg并使肿瘤引发PD-1阻断的一组图。图5a、5b和5c显示了肿瘤生长(图5a)(对照,n=4;α-CD36Ab,n=6),所示组织的CD4+T细胞中FoxP3+Treg的百分比(图5b)(对照,n=4;α-CD36Ab,n=4),以及来自用所示处理处理的荷YUMM1.7黑色素瘤B6小鼠的所示组织分离的Treg中切割的胱天蛋白酶-3的表达(图5c)(对照,n=4;α-CD36Ab,n=5)。图5d显示用对照媒介物(对照)或α-CD36mAb处理的荷YUMM1.7黑色素瘤WT和TregCD36-/-小鼠的肿瘤生长(WT+对照,n=12;WT+α-CD36 Ab,n=10;TregCD36-/-+对照,n=11;TregCD36-/-+α-CD36 Ab,n=10)。图5e显示了用所示处理处理的荷YUMM1.7黑色素瘤WT和TregCD36-/-小鼠的肿瘤生长(WT+对照,n=12;WT+α-CD36 Ab,n=10;TregCD36-/-+对照,n=11;TregCD36-/-+α-CD36 Ab,n=10)。图5f和5g显示了利用所示处理来处理的荷YUMM1.7黑色素瘤WT和TregCD36-/-小鼠的肿瘤生长(图5f)和Kaplan-Meier生存曲线(图5g)(WT,n=5;TregCD36-/-,n=4;WT+α-PD1,n=4;TregCD36-/-+α-PD1,n=5)。生存时间的差异通过对数秩(Mantel–Cox)检验分析。图5h显示了用所示处理处理的可诱导的荷Braf/Pten黑色素瘤小鼠的肿瘤生长(对照,n=10;α-PD1,n=11;α-CD36,n=11;α-CD36+αPD-1,n=11)。箭头指示处理日期。数据是三个独立实验的代表性结果(图5a、5b和5c)或来自至少两个独立实验的累积结果(图5d、5e、5f、5g和5h)。每个符号代表一个个体。数据为平均值±S.D.(图5b和5c)或±S.E.M.(图5a、5d、5e和5f)并通过双尾未配对的学生t检验进行分析。*P<0.05,**P<0.01,ns,无显著性差异。
图6a、6b、6c和6d是显示靶向CD36释放宿主抗肿瘤免疫的一组图。图6a、6b、6c和6d显示了每克肿瘤FoxP3+Treg的绝对数量(每组n=10)(图6a)、肿瘤浸润T细胞中CD8+T细胞的百分比(每组n=19)(图6b)和来自用所示处理处理的荷YUMM1.7黑色素瘤B6小鼠的总的肿瘤浸润CD8+T细胞中的代表性图和所示产生细胞因子的CD8+T细胞的百分比(图6c)和总的肿瘤浸润CD4+T细胞中CD4+T细胞的代表性图和百分比(图6d)(每组n=10)。
图7a、7b、7c、7d、7e、7f、7g和7h是显示检查点阻断抑制剂的协同作用的一组图。图7a显示了在所示组织的CD4+T细胞中FoxP3+Treg的百分比(对照,n=4;α-CTLA4 mAb,n=4;α-CD36 mAb,n=4)。每个符号代表一个个体。数据为平均值±S.D.并通过双尾未配对的学生t检验进行分析。*P<0.05,**P<0.01。图7b、7c、7d、7e、7f、7g和7h显示了利用所示处理处理的荷YUMM1.7黑色素瘤B6小鼠的肿瘤生长和Kaplan-Meier生存曲线(对照,n=10;α-PD1,n=10;α-CTLA4,n=7;α-CD36,n=11;α-CTLA4+αPD-1,n=7,α-CD36+αPD-1,n=11)。头指示处理日期。每个符号代表一个个体。
发明详述
所公开的用于调节受试者中的肿瘤内调节性T(Treg)细胞并抑制肿瘤生长的方法部分基于意外发现:CD36的Treg特异性消除减少了肿瘤内Treg的积累并抑制肿瘤生长。有利地,Treg特异性CD36缺乏症不导致自身免疫,而CD36缺陷性(deficient)Treg细胞保持其抑制活性,例如在抑制CD4T细胞诱导的炎症性肠病中。
通过抑制肿瘤特异性T细胞(例如CD8+T细胞毒性细胞)攻击肿瘤细胞,Treg细胞的诱导认为是针对肿瘤相关抗原的免疫应答失败的根本原因。因此,预期通过失活Treg细胞,可以避免免疫系统的抑制,并且免疫系统将能够发起攻击原发性和转移性肿瘤的响应。
本公开表明,CD36缺乏可以诱导Treg细胞失活。CD36是一种表面糖蛋白,也称为脂肪酸转位酶(FAT)。CD36参与炎症反应并调节多种功能,例如脂质吸收,脂质储存和脂质利用(Glatz和Luiken,JLR,2018)。肿瘤浸润T细胞具有异常高的脂肪酸摄取,高的细胞内脂质含量和高的CD36表达水平(Yin et al.,J Immunol,2016;Cui and Kaech,Cancer ImmunolRes,2016)。CD36表达通过PPAR信号转导调节其线粒体适应性来支持肿瘤内Treg细胞的存活。因此,肿瘤内Treg细胞中CD36的高表达水平通过干预代谢调节来协调(orchestrate)肿瘤中Treg细胞的代谢适应,并通过抑制抗肿瘤免疫应答进一步促进肿瘤生长。因此,靶向CD36或PPAR信号途径可能代表一种有吸引力的治疗方法,以用于调节肿瘤内Treg细胞并抑制肿瘤生长。
I.降低肿瘤内Treg细胞数量并增加肿瘤内细胞毒性T细胞数量的方法
本公开提供了降低受试者中肿瘤内Treg细胞数量的方法。该方法可以包括向受试者施用有效量的CD36抑制剂或PPARβ抑制剂。
本公开还提供了增加受试者中肿瘤内细胞毒性T细胞数量的方法。该方法可以包括向所述受试者施用有效量的CD36抑制剂。在一些实施方案中,该方法可以包括向所述受试者施用有效量的PPARβ抑制剂。
如本文所用,“受试者”指人类或非人类哺乳动物。非人类哺乳动物包括,例如,牲畜和宠物,例如绵羊、牛、猪、犬、猫和鼠类哺乳动物。在某些实施方案中,受试者是人类。“组织特异性”启动子是这样的核苷酸序列,当与编码或由基因指定的多核苷酸可操作地连接时,仅当该细胞是对应于启动子的该组织类型的细胞时,该基因产物才在细胞中大体上产生。
如本文所用,“肿瘤内”是指位于肿瘤细胞胰岛内的T细胞(即,与明显恶性的上皮细胞并列),而癌周围T细胞位于包围并浸润肿瘤的基质中。因此,T细胞可以位于肿瘤内,但是由于与基质恶性细胞而不是实际的恶性细胞紧密关联,因此它可能不被视为肿瘤内T细胞。可以使用本领域已知的用于检测保留肿瘤结构的T细胞的任何方法来确定其是否其在肿瘤内。
如本文所用,术语“调节性T细胞”或“Treg细胞”是指具有抑制特性的CD4+CD25+FoxP3+T细胞。如本文所用,术语“辅助T细胞”是指CD4 T细胞。辅助T细胞(例如Th1和Th2)识别与MHC II类分子结合的抗原并产生不同的细胞因子。如本文所用,本文所用的术语“细胞毒性T细胞”是指CD8+T细胞。细胞毒性T细胞识别与MHC I类分子结合的抗原。
Treg细胞可以包括表达CD4、CD25和FOXP3的T细胞,例如CD4+、CD4+CD25+、CD4+Foxp3+调节性T细胞。细胞毒性T细胞,也称为杀伤性T细胞,可以包括CD8+T细胞。
CD36抑制剂可包括但不限于核酸分子(例如,酶促核酸分子、反义核酸分子、三链寡核苷酸、dsRNA、ssRNA、RNAi、siRNA、适配体、2,5-A嵌合体)、脂质、类固醇、肽、蛋白质、等位酶、抗体、单克隆抗体、人源化单克隆抗体和小分子(例如抗病毒化合物)。类似地,PPARβ抑制剂可包括但不限于核酸分子(例如,酶促核酸分子、反义核酸分子、三链寡核苷酸、dsRNA、ssRNA、RNAi、siRNA、适配体、2,5-A嵌合体)、脂质、类固醇、肽、蛋白质、等位酶、抗体、单克隆抗体、人源化单克隆抗体和小分子(例如抗病毒化合物)。例如,抗CD36抗体可以是人抗体、人源化抗体、嵌合抗体或双特异性抗体。小分子CD36抑制剂的非限制性实例可包括AP-5258、AP5055、EP-80317、MPE-002、CHEML1789142、CHEML1789302、CHEML1789297、CHEML1789141、CHEML1789270、CHEML1789308。
小分子PPARβ抑制剂的非限制性实例可包括FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
在一些实施方案中,降低受试者中肿瘤内Treg细胞数量的方法可以包括向所述受试者施用CD36抑制剂或PPARβ抑制剂联合额外的治疗剂(例如抗癌剂)。
额外的治疗剂可以是免疫检查点调控剂,例如对免疫检查点特异性的抗体。免疫检查点的实例可包括但不限于CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。免疫检查点调控剂的非限制性实例包括伊匹单抗(ipilimumab)、曲美单抗(tremelimumab)派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、匹地利珠单抗(pidilizumab)、MPDL3280A、MEDI4736、BMS-936559、MSB0010718C和AMP-224。
CD36抑制剂、PPARβ抑制剂或额外的治疗剂可以在任何适当的载体中同时或依次施用,用于口服、局部或肠胃外施用。
CD36抑制剂、PPARβ抑制剂或额外的治疗剂可以以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
CD36抑制剂、PPARβ抑制剂或额外的治疗剂可以制备为药物组合物。药物组合物可以以适合于口服、直肠、阴道、肠胃外、局部、肺、鼻内、颊或眼科施用途径的制剂制备,包装或出售。该制剂可以包括投射(projected)纳米颗粒、脂质体制剂、含有活性成分的重新密封的红细胞以及基于免疫学的制剂。例如,配制用于肠胃外施用的药物组合物可以包括与药学上可接受的载体(例如,无菌水或无菌等渗盐水)组合的活性成分(例如,CD36抑制剂,PPARβ抑制剂)。
可注射制剂可以以单位剂型制备、包装或出售,例如在安瓿或含有防腐剂的多剂量容器中。肠胃外施用的制剂包括但不限于混悬剂、溶液、在油性或水性媒介物中的乳剂、糊剂和可植入的持续释放或可生物降解的制剂。此类制剂可以进一步包括一种或多种额外的成分,例如悬浮剂、稳定剂或分散剂。在用于肠胃外施用的制剂的一个实例中,以干燥(即粉末或颗粒)形式提供活性成分,以在肠胃外施用重构的组合物之前用合适的媒介物(例如,无菌无热原的水)重构。
Ⅱ.抑制肿瘤生长的方法
本公开还提供了在患有癌症的受试者中抑制肿瘤生长的方法。该方法可以包括向受试者单独或与额外的治疗剂(例如抗癌剂)组合施用治疗有效量的CD36抑制剂。备选地或另外,该方法可以包括向受试者单独或与额外的治疗剂(例如抗癌剂)组合施用治疗有效量的PPARβ抑制剂。
CD36抑制剂可包括但不限于核酸分子(例如,酶促核酸分子、反义核酸分子、三链寡核苷酸、dsRNA、ssRNA、RNAi、siRNA、适配体、2,5-A嵌合体)、脂质、类固醇、肽、蛋白质、等位酶、抗体、单克隆抗体、人源化单克隆抗体和小分子(例如抗病毒化合物)。类似地,PPARβ抑制剂可包括但不限于核酸分子(例如,酶促核酸分子、反义核酸分子、三链寡核苷酸、dsRNA、ssRNA、RNAi、siRNA、适配体、2,5-A嵌合体)、脂质、类固醇、肽、蛋白质、等位酶、抗体、单克隆抗体、人源化单克隆抗体和小分子(例如抗病毒化合物)。小分子PPARβ抑制剂的非限制性实例可包括FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
额外的治疗剂可以是免疫检查点调控剂,例如对免疫检查点特异性的抗体。免疫检查点的实例可包括但不限于CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。免疫检查点调控剂的非限制性实例包括伊匹单抗(ipilimumab)、曲美单抗(tremelimumab)派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、匹地利珠单抗(pidilizumab)、MPDL3280A、MEDI4736、BMS-936559、MSB0010718C和AMP-224。
在一些实施方案中,额外的治疗剂可包括一种或多种抗肿瘤/抗癌剂,包括化学治疗剂和免疫治疗剂。
“化学治疗剂”是用于治疗癌症的化合物。化学治疗剂的实例包括烷化剂类(alkylating agent),例如噻替哌(thiotepa)和环磷酰胺(CYTOXANTM);烷基磺酸盐(alkylsulfonate),例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridine),例如苯并多巴(benzodopa)、卡波醌(carboquone)、甲基多巴(methyldopa)和乌多巴(uredopa);乙亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三亚乙基蜜胺(triethylenemelamine)、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)和三羟甲基密胺(trimethylolomelamine);多聚乙酰类(acetogenin)(特别是布拉它辛(bullatacin)和布雷他辛酮(Bullatacinone));喜树碱(camptothecin)(包括合成的类似物拓扑替康(topotecan));苔藓抑素(bryostatin);卡利他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(cryptophycin)(尤其是念珠藻素1和念珠藻素8);海兔毒素(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物,KW-2189和CBI-TMI);五加素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类(nitrogen mustard),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、二氯甲基二乙胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼氮芥(prednimustine)、曲洛磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosourea),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素类,例如烯二炔类(enediyne)抗生素(例如,加利车霉素(calicheamicin),参见例如,AgnewChem.Intl.Ed.Engl.33:183-186(1994);达内霉素(dynemicin),包括达内霉素A;埃斯培拉霉素(esperamicin);以及新卡司他汀(neocarzinostatin)发色团和相关的色蛋白烯二炔(chromoprotein enediyne)抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(Authramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素(cactinomycin)、卡拉比星(carabicin)、卡米诺霉素(caminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、放线菌素(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、阿霉素(doxorubicin)(包括吗啉代-阿霉素(morpholino-doxorubicin)、氰基吗啉代-阿霉素(cyanomorpholino-doxorubicin)、2-吡咯啉-阿霉素(2-pyrrolino-doxorubicin)和脱氧阿霉素(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素类(olivomycins)、培洛霉素(peplomycin)、泼非霉素(potfiromycin)、嘌呤霉素(puromycin)、奎那霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢药,诸如氨甲蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如迪诺特宁(denopterin)、氨甲蝶呤(methotrexate)、蝶罗呤(pteropterin)、曲美沙特(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、噻咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如环胞苷(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,诸如卡芦睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);贝斯布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依洛尼塞(elfomithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);乙环氧啶(etoglucid);硝酸镓;羟基脲;蘑菇多糖(lentinan);氯尼达明(lonidainine);类美登素类(maytansinoid),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基肼(2-ethylhydrazide);丙卡巴肼(procarbazine);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofuran);锗螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺(2,2’,2”-trichlorotriethylamine);单端孢霉烯(trichothecene)(尤其T-2毒素、粘液霉素A(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamide);噻替派(thiotepa);紫杉烷类(taxoid),例如紫杉醇(Bristol-Myers Squibb Oncology,Princeton,N.J.)和多西他赛(doxetaxel)(Rhone-Poulenc Rorer,Antony,法国);苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);氨甲蝶呤(methotrexate);铂类似物,诸如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);丝裂霉素C(mitomycin C)、米托蒽醌(mitoxantrone)、长春新碱(vincristine);长春瑞滨(vinorelbine);诺消灵(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨基喋呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);维甲酸(retinoicacid);卡培他滨(capecitabine);以及任何上述的药学上可接受的盐、酸或衍生物。该定义中还包括用于调节或抑制激素对肿瘤的作用的抗激素药,诸如抗雌激素,包括例如他莫西芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香酶抑制4(5)-咪唑类(4(5)-imidazole)、4-羟基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene)(Fareston);和抗雄激素,诸如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及任何上述的药学上可接受的盐、酸或衍生物。
“免疫治疗剂”是用于治疗癌症的生物制剂。免疫治疗剂的实例包括阿特珠单抗atezolizumab、阿维单抗(avelumab)、博纳吐单抗(Blinatumomab)、达雷木单抗(daratumumab)、cemiplimab、德瓦鲁单抗(durvalumab)、埃罗妥珠单抗(elotuzumab)、laherparepvec、伊匹单抗(ipilimumab)、纳武单抗(nivolumab)、奥滨尤妥珠单抗(obinutuzumab)、奥法木单抗(ofatumumab)、派姆单抗(pembrolizumab)和talimogene。
该方法可以包括向受试者施用包含CD36抑制剂、PPARβ抑制剂、免疫检查点调控剂或其任意组合的组合物。额外的治疗剂,CD36抑制剂和/或PPARβ抑制剂可以在任何适当的载体中同时或依次施用,用于口服、局部或肠胃外施用。CD36抑制剂、PPARβ抑制剂或免疫检查点调控剂可以以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
癌症可包括但不限于贲门癌(cardiac cancer),包括例如肉瘤,例如血管肉瘤、纤维肉瘤、横纹肌肉瘤和脂肪肉瘤;粘液瘤;横纹肌瘤;纤维瘤;脂肪瘤和畸胎瘤;肺癌,包括例如支气管癌,例如鳞状细胞癌、未分化的小细胞、未分化的大细胞和腺癌;肺泡和支气管癌;支气管腺瘤;肉瘤;淋巴瘤;软骨性错构瘤;和间皮瘤;胃肠道癌,包括例如食道癌,例如鳞状细胞癌、腺癌、平滑肌肉瘤和淋巴瘤;胃癌,例如癌瘤、淋巴瘤和平滑肌肉瘤;胰腺癌,例如导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤和血管活性肠肽瘤(vipoma);小肠癌,例如腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤(Kaposi's sarcoma)、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤和纤维瘤;大肠癌,例如腺癌、管状腺瘤、绒毛腺瘤、错构瘤和平滑肌瘤;泌尿生殖道癌,包括例如肾癌,例如腺癌、威尔姆氏肿瘤(Wilm's tumor)(肾胚细胞瘤)、淋巴瘤和白血病;膀胱和尿道癌,例如鳞状细胞癌、移行细胞癌和腺癌;前列腺癌,例如腺癌和肉瘤;睾丸癌,例如精原细胞瘤、畸胎瘤、胚胎性癌,畸胎癌、绒毛膜癌、肉瘤,间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤和脂肪瘤;肝癌,包括例如肝细胞瘤,例如肝细胞癌;肝内胆管癌(cholangiocarcinoma);肝母细胞瘤;血管肉瘤;肝细胞腺瘤;和血管瘤;骨癌包括例如,成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤(Ewing'ssarcoma)、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨性外生骨疣(osteocartilaginous exostoses))、良性软骨瘤、软骨母细胞瘤,软骨粘膜纤维瘤(chondromyxofibroma)、类骨质骨瘤和巨细胞瘤;神经系统癌症包括例如颅骨癌,例如骨瘤、血管瘤、肉芽肿瘤、黄瘤和变形性骨炎;脑膜癌,例如脑膜瘤、血管肉瘤和神经胶质瘤;脑癌,例如星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形胶质母细胞瘤、少突胶质细胞瘤、神经鞘瘤、视网膜母细胞瘤和先天性肿瘤;脊髓癌,例如神经纤维瘤、脑膜瘤、神经胶质瘤和肉瘤;妇科癌症,包括例如子宫癌,例如子宫内膜癌;宫颈癌,例如宫颈肿瘤和癌前宫颈发育不良;卵巢癌,例如卵巢肿瘤,包括浆液性囊腺癌、粘液性囊腺癌、未分类癌(unclassified carcinoma),颗粒-鞘细胞瘤(granulosa-thecalcell tumor),Sertoli-Leydig细胞瘤、无形细胞瘤和恶性畸胎瘤;外阴癌,例如鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤和黑色素瘤;阴道癌,例如透明细胞癌、鳞状细胞癌、葡萄状肉瘤和胚胎性横纹肌肉瘤;输卵管癌,例如癌瘤;血液系统癌症,包括例如血癌,例如急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤和骨髓增生异常综合征、霍奇金氏(Hodgkin's)淋巴瘤、非霍奇金淋氏巴瘤(恶性淋巴瘤)和瓦尔登斯特伦氏巨球蛋白血症;皮肤癌包括例如恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波济氏(Kaposi's)肉瘤、增生性痣(molesdysplastic nevi)、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤和牛皮癣;乳腺癌,包括例如导管癌、小叶癌、炎性乳腺癌、髓样癌、粘液性(胶体)癌、乳腺湿疹样癌(Paget's disease ofthe breast)、小管癌、叶状肿瘤、化生癌、肉瘤、微毛细血管癌和腺样囊性癌;和肾上腺癌,包括例如神经母细胞瘤。
癌症可以是可能转移或可能不转移的实体瘤。像白血病一样,癌症也可能以弥漫性组织发生。
D36抑制剂、PPARβ抑制剂或额外的治疗剂可以在与疾病或病症相关的症状表现之前或之后施用于患者。此外,可以每天或顺序施用数个分剂量以及交错剂量,或者该剂量可以连续输注或可以是团注。此外,治疗制剂的剂量可以根据治疗或预防情况的紧急程度成比例地增加或减少。
可以使用已知程序,以有效治疗患者疾病或病症的剂量和时间段对受试者实施施药。实现治疗效果所必需的治疗化合物的有效量可以根据因素而变化(例如所采用的特定化合物的活性;施用时间;该化合物的排泄速率;治疗的持续时间;其他药物,化合物或与该化合物组合使用的材料;疾病或病症的状态、年龄、性别、体重、病况、一般健康状况以及所治疗患者的既往病史,以及医学领域众所周知的类似因素)。可以调整给药方案以提供最佳的治疗响应。例如,如治疗情况的紧急状态所示,可以每天施用数个分剂量或可以成比例地减少剂量。本发明的治疗化合物的有效剂量范围的非限制性实例是约0.01至50mg/kg体重/每天。本领域普通技术人员将能够研究相关因素并确定治疗化合物的有效量而无需过度实验。
施用可以每天频繁进行几次,或者也可以不那么频繁施用,例如每天一次、每周一次、每两周一次、每月一次、或者甚至更不频繁,例如每几个月一次或甚至一年或更短时间一次。应当理解,在非限制性实例中,每天给药的化合物的量可以每天、每隔一天、每2天、每3天、每4天或每5天施用。例如,每隔一天施用,则可以在星期一开始每天5mg的剂量,在星期三施用第一随后每天5mg剂量,在星期五施用第二随后每天5mg剂量,依此类推。剂量的频率对技术人员而言是显而易见的,并且将取决于许多因素,例如但不限于所治疗疾病的类型和严重性、动物的类型和年龄等。
施用途径可包括吸入、口服、鼻、直肠、肠胃外、舌下、经皮、经粘膜(如舌下、舌、经口、经尿道、经阴道(如经阴道和经阴道)、(内)经鼻、(经)直肠)、膀胱内、肺内、十二指肠内、胃内、鞘内、皮下、肌内、皮内、颅内、动脉内、静脉内、支气管内、吸入和局部施用。
如本文所用,“肠胃外施用”包括特征在于对受试者的组织进行物理破坏以及通过组织中的破坏对药物组合物的施用的任何施用途径。肠胃外施用因此包括但不限于通过注射组合物,通过外科切口给药组合物,通过穿透组织的非外科伤口给药组合物等方式施用药物组合物。特别地,肠胃外施用还可以包括但不限于颅内、皮下、静脉内、腹膜内、肌内、胸骨内注射和肾透析输注技术。
可以以各种合适的组合物和剂型提供CD36抑制剂、PPARβ抑制剂或额外的治疗剂,包括例如片剂、胶囊剂、囊片、丸剂、囊形片、锭剂、分散剂、混悬剂、溶液、糖浆、颗粒剂、珠子、经皮贴剂、凝胶剂、粉剂、丸剂、糊剂、喉糖(lozenge)、乳膏、糊剂(paste)、膏药、乳液、薄片剂(disc)、栓剂、鼻腔或口服液施用的液体喷雾、吸入用干粉或雾化制剂、膀胱内施用的组合物和制剂等等。应当理解,可用于本发明的制剂和组合物不限于本文描述的特定制剂和组合物。对于口服给药,特别合适的是片剂、糖衣丸、液体、滴剂、栓剂或胶囊、囊片和囊形片。其他适合口服施用的制剂包括但不限于粉末或颗粒制剂、水性或油性悬浮液、水性或油性溶液、糊剂、凝胶剂、牙膏、漱口剂、包衣、口服灌洗剂或乳剂。
Ⅲ.定义
为了帮助理解根据本公开的组合物和方法的详细描述,提供一些明确的定义以促进本公开的各个方面的明确公开。除非另有定义,否则本文中所用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解的相同含义。
如本文所用,“PPARβ”和“PPARδ”在本公开中可互换使用并且指相同的PPAR受体。
如本文所用,“受试者”是指哺乳动物,包括人。进行诊断或治疗的非人类动物可包括例如灵长类动物、牛、山羊、绵羊、马、狗、猫、小鼠、大鼠等。
如本文所用,术语“治疗”是指防止疾病发展或改变疾病的病理或症状而进行的干预。因此,“治疗”是指治疗性治疗和预防性或预防性措施。需要治疗的人包括已经患有该疾病的人以及要预防该疾病的人。在肿瘤(例如,癌症)治疗中,治疗剂可直接降低肿瘤细胞的病理学,或使肿瘤细胞更易于受到其他治疗剂(例如,放射和/或化学疗法)治疗的影响。
因此,“治疗”可以包括压制、抑制、预防、治疗或其组合。治疗尤其是指增加持续进展的时间、加快缓解、诱导缓解、增加缓解、加快恢复、增加替代疗法的功效或降低替代疗法的抵抗力,或其组合。“压制”或“抑制”尤其是指延迟症状发作、防止疾病复发、减少复发发作的次数或频率、增加症状发作之间的潜伏期、减少症状的严重程度、减少急性发作的严重程度、减少症状的数目、减少疾病相关症状的发生率、减少症状的潜伏期、改善症状、减少继发性症状、减少继发性感染、延长患者生存期或其组合。
如本文所用,术语“调节”或“调节中”是指任何提及的活动例如,增加、增强、增加、加强、激动(充当激动剂)、促进、减少、降低、抑制阻断、或拮抗(充当拮抗剂)。与基线值相比,调节可以使活性增加超过1倍、2倍、3倍、5倍、10倍、100倍等。调节也可以将其活性降低到基线值以下。
术语“预防(prevent)”、“预防中(preventing)”、“预防(prevention)”、“预防性治疗”等是指降低未患有但有风险或易患疾病或病症的受试者发生疾病或病症的可能性。
如本文所用,术语“疾病”通常是同义词,并且与术语“病症”和“病状”(如医学病状)可互换使用,因为它们均反映出人体或动物体的异常病状或损害正常功能的部位之一,通常表现为明显的体征和症状,导致人或动物的生活时间或生活质量降低。
在本文中所用的术语“减少(decrease)”、“降低(reduced)”、“降低(reduction)”、“减少(decrease)”或“抑制”通常全部用来意指减少统计学上显著的量。但是,为避免疑问,“降低”、“降低”或“减少”或“抑制”意指与参考水平相比减少至少10%,例如与参考水平相比减少至少约20%、或至少约30%、或至少约40%、或至少约50%、或至少约60%、或至少约70%、或至少约80%、或至少约90%或以上且包括减少100%(例如,与参考样品相比没有水平),或在10-100%之间的任何减少。
本文所用的术语“增加(increased)”、“增加(increase)”或“增强”或“激活”通常全部用来意指增加统计学上显著的量;为避免任何疑问,术语“增加(increased)”、“增加(increase)”或“增强”或“激活”意指与参考水平相比至少10%的增加,例如与参考水平相比至少约20%、或至少约30%、或至少约40%、或至少约50%、或至少约60%、或至少约70%、或至少约80%、或至少约90%或以上的增加且包括增加100%或10-100%之间的任何增加,或与参考水平相比增加至少约2倍、或至少约3倍、或至少约4倍、或至少约5倍或至少约10倍、或在2倍至10倍之间或更大的任何增加。
术语“有效量(effective amount)”、“有效剂量(effective dose)”或“有效剂量(effective dosage)”定义为足以达到或至少部分达到期望效果的量。药物或治疗剂的“治疗有效量”或“治疗有效剂量”是当单独使用或与另一种治疗剂组合使用时可促进疾病消退(通过疾病症状的严重程度的降低,疾病无症状时期的频率和持续时间的增加来证明)或由于疾病困扰而导致的损伤或残疾的预防的药物的任意量。药物的“预防有效量”或“预防有效剂量”是当单独或与另一种治疗剂组合施用于处于发生疾病或患有疾病复发的风险的受试者,以抑制疾病的发展或复发的药物的量。治疗或预防剂促进疾病消退或抑制疾病发展或复发的能力可以使用本领域技术人员已知的多种方法来评估,例如在临床试验期间的人类受试者中,在可预测人类功效的动物模型系统中,或通过在体外测定中测定药剂的活性。
通常表示剂量与体重有关。因此,以[g、mg或其他单位]/kg(或g、mg等)表示的剂量通常是指[g、mg或其他单位]“每kg(或g、mg等)体重”,即使未明确提及“体重”术语。
术语“试剂”在本文中用于表示化合物、化合物的混合物、生物大分子(例如核酸、抗体、蛋白质或其部分,例如肽)或由生物材料(例如细菌、植物、真菌或动物(尤其是哺乳动物)细胞或组织)制成的提取物。此类试剂的活性可以使其适合作为“治疗剂”,其是在受试者中局部或系统起作用的生物学、生理学或药理学活性物质(或物质)。
术语“治疗剂(therapeutic agent)”、“有治疗能力的药剂(therapeutic capableagent)”或“治疗剂(treatment agent)”可互换使用,并且是指在施用于受试者时赋予某些有益作用的分子或化合物。有益效果包括诊断确定的实现;改善疾病、症状、病症或病理状况;降低或预防疾病、症状、病症或病状的发作;并且通常可以抵抗疾病、症状、病症或病理状况。
如本文所用,“治疗有效量”或“有效量”是指无毒但提供所需生物学结果的足够试剂量。该结果可以是疾病或病症的体征、症状或病因的降低和/或减轻,或生物系统的任何其他期望的改变。在任何情况下,本领域普通技术人员之一可以使用常规实验确定适当的治疗量。
除非在上下文中另外清楚,否则本文所用的“联合”疗法意指在涵盖以协调的方式施用两种或更多种治疗剂,并且包括但不限于同时给药。具体而言,组合疗法涵盖共同施用(例如,共同制剂的施用或分开的治疗组合物的同时施用)和连续或顺序施用,前提是一种治疗剂的施用以某种方式取决于另一种治疗剂的施用。例如,仅在已经施用了不同的治疗剂并且允许其作用规定的时间之后才施用一种治疗剂。参见,例如,Kohrt et al.(2011)Blood117:2423。
如本文所用,术语“消减”是指降低或消除给定类型的细胞的功能,使细胞无效、部分或完全消除细胞的增殖、和/或杀死细胞。
如本文所用,术语“抗体”(Ab)包括单克隆抗体、多克隆抗体、多特异性抗体(例如,双特异性抗体和多反应性抗体)和抗体片段。因此,在本说明书中任何上下文中使用的术语“抗体”旨在包括但不限于任何特异性结合成员,免疫球蛋白类别和/或同种型(例如,IgG1、IgG2、IgG3、IgG4、IgM、IgA、IgD、IgE和IgM);与其生物学相关的片段或其特异性结合成员,包括但不限于Fab、F(ab')2、Fv和scFv(单链或相关实体(entity))。在本领域中应理解,抗体是具有通过二硫键相互连接的至少两条重(H)链和两条轻(L)链的糖蛋白,或其抗原结合部分。重链由重链可变区(VH)和重链恒定区(CH1、CH2和CH3)组成。轻链由轻链可变区(VL)和轻链恒定区(CL)组成。重链和轻链的可变区均包含构架区(FWR)和互补决定区(CDR)。四个FWR区相对保守,而CDR区(CDR1、CDR2和CDR3)代表高变区,并从NH2末端到COOH末端排列如下:FWR1、CDR1、FWR2、CDR2、FWR3、CDR3和FWR4。重链和轻链的可变区含有与抗原相互作用的结合结构域,而根据同种型,恒定区可以介导免疫球蛋白与宿主组织或因子的结合。如本文所用,在“抗体”的定义中还包括嵌合抗体、人源化抗体和重组抗体,从转基因非人动物产生的人抗体,以及使用技术人员可用的富集技术选自文库的抗体。
如本文所用,术语“体外”是指在人工环境中例如在试管或反应容器中,在细胞培养物中等而不是在多细胞生物体内发生的事件。
如本文所用,术语“体内”是指在诸如非人类动物的多细胞生物体内发生的事件。
在此应注意的是,如在本说明书和所附权利要求书中所使用的,单数形式的“一个(a)”、“一种(an)”和“该(the)”包括复数引用,除非上下文另外明确指出。
除非另外指出,否则术语“包括”、“包含”、“含有”或“具有”及其变体旨在涵盖其后列出的项目及其等同形式以及额外的主题。
重复使用短语“在一个实施方案中”、“在各种实施方案中”、“在一些实施方案中”等。此类短语不一定指代相同的实施方案,但是除非上下文另外指出,否则它们可能。
术语“和/或”或“/”意指与该术语相关联的任何一个项目、这些项目的任何组合或所有项目。
词“大体上”不排除“完全”,例如,“大体上不含”Y的组合物可能完全不含Y。必要时,可以从本发明的定义中省略词“大体上”。
如本文所用,术语“每个”当用于参考项目的集合时,旨在标识该集合中的单个项目,但是不一定指代该集合中的每个项目。如果明确的公开或上下文另有明确规定,则可能会发生例外。
除非另外要求,否则本文提供的任何和所有示例或示例性语言(例如,“诸如”)的使用仅旨在更好地阐明本发明,并且不对本发明的范围构成限制。说明书中的任何语言都不应解释为指示任何未要求保护的要素对于实施本发明是必不可少的。
除非本文另外指出或上下文明显矛盾,否则本文描述的所有方法均以任何合适的顺序进行。关于所提供的任何方法,该方法的步骤可以同时发生或顺序发生。当该方法的步骤顺序发生时,除非另有说明,否则这些步骤可以以任何顺序发生。
在方法包含步骤的组合的情况下,步骤的每个和每个组合或子组合都涵盖在本公开的范围内,除非本文另外指出。
本文引用的每个出版物、专利申请、专利和其他参考文献均以与本公开内容不矛盾的程度通过引用以其全部并入。仅在本发明提交日期之前提供本文公开的出版物以供其公开。本文中的任何内容均不应解释为承认本发明无权凭借在先发明而早于此类出版物。此外,提供的公开日期可能与实际公开日期不同,实际公开日期可能需要独立确认。
应当理解,本文描述的实例和实施方案仅用于说明目的,并且鉴于其的各种修改或改变将被建议给本领域技术人员,并且将被包括在本申请的精神和范围以及所附权利要求的范围内。
Ⅳ.实施例
实施例1:本示例描述了后续实施例中要使用的材料和方法。
小鼠。C57BL/6/J、FoxP3YFP-Cre、Rag1–/–(B6.129S7-Rag1tm1Mom/J)小鼠购自Jackson实验室。如前所述产生CD36fl/fl小鼠(Son,N.H.et al.J Clin Invest128,4329-4342(2018).)。如Dammone,G等人所述产生PPARγfl/fl和PPARβfl/fl小鼠(Dammone,G.etal.International journal of molecular sciences 19(2018))。Dankort等人(Dankortet al.Nature Genetics volume 41,pages544–552(2009))描述了BRafCA;Tyr::CreER;Ptenlox4-5(Braf/Pten)。DuPage等人(DuPage et al.Nature Protocols第四卷,第1064–1072页(2009))描述了NSCLC的K-rasLSL-G12D/+/p53fl/fl条件小鼠模型。将动物饲养在洛桑大学的无特定病原体设施中,且所有实验研究均根据《瑞士动物福利条例》实施的准则和规定批准和实施。
细胞系和体外培养。在Meeth等人(Meeth,K.,et al.Pigment cell&melanomaresearch 29,590-597,(2016))中描述了YUMM1.7黑色素瘤细胞系。在具有10%胎牛血清和1%青霉素-链霉素的DMEM中培养YUMM1.7和B16-ova黑色素瘤细胞系,并在指数生长期用于实验。Hoves等人描述了MC38结肠腺癌细胞系(Hoves et al.Journal of ExperimentalMedicine,215(3)859-876(2018))。MC38细胞系维持在具有10%的胎牛血清和1%青霉素-链霉素的IMDM中。
癌细胞条件培养基和iTreg培养。通过在补充有10%FBS、10ng/ml TGFβ和50U/mlIL-2的RMPI培养基中用与抗CD3和抗CD28单克隆抗体(ThermoFisher)缀合的Dynabeads激活幼稚CD4+T细胞三天来产生iTreg。然后将活化的CD4+T细胞在加入10%FBS和50U/ml IL-2的RPMI培养基中维持另外2天。首先使用FACS细胞分选仪分选分化的iTreg,然后在指定的培养条件下温育48h。然后分别通过活/死染色和ELISA试剂盒确定iTreg的存活和NAD/NADH水平。为了在用PPARβ激动剂处理的CD36-KO iTreg中进行NAD/NADH测量,将分选的iTreg在DMSO或GW50156存在的癌细胞条件培养基中培养48小时。用补充有2mM葡萄糖、10mM谷氨酰胺、10%透析FBS、0.1%β-ME和所示乳酸水平的RPMI 1640培养基(BiologicalIndustries)制备用于iTreg体外处理的对照RPMI。通过将YUMM1.7细胞(70-80%密度)与上述对照RPMI一起温育18小时来收集YUMM1.7癌细胞条件培养基。然后,收集培养基并在2000rpm下离心15分钟以除去碎片和癌细胞,作为癌细胞条件培养基。根据制造商的说明,在Treg培养之前,将上述收集的YUMM1.7癌细胞条件培养基用CleanasciteTM试剂(BiotechSupport Group)处理,体积比为1:5。
离体抑制测定。使用阴性选择试剂盒(MojoSort小鼠CD8 T细胞分离试剂盒,Biolegend)富集来自Ly5.1小鼠脾脏的CD8 T细胞,并在37℃下用CellTraceTMCFSE细胞增殖试剂盒(ThermoFisher)染色15分钟。将1×104个CD8细胞接种到96孔圆板中,所述96孔圆板中有由50U/ml IL-2组成的RPMI培养基。根据指定的Treg:Teff比率,添加从FoxP3YFP-Cre或TregCD36-/-小鼠的脾细胞或TIL中分离的CD44+/YFP+Treg(CD45.2+)。然后,除阴性对照组外,将抗CD3/CD28缀合的Dynabeads(ThermoFisher)补充到培养物中。将细胞在37℃、5%CO2下温育72小时,然后用流式细胞仪分析通过CFSE稀释确定CD8+T细胞的增殖。
肿瘤植入(engraftment)和荷瘤小鼠的处理。为了诱导肿瘤,如前所述,对3周大的Braf/Pten小鼠在皮肤表面用4-羟基他莫昔芬(hydroxytamoxifen)处理以诱导肿瘤形成(Ho,P.C.et al.Cancer Res 74,3205-3217(2014))。对于肿瘤植入,将5×104个YUMM1.7、B16-OVA细胞或一百万个MC38肿瘤细胞皮下注射到50μl PBS中。肿瘤植入或指定处理后每隔2-3天测量肿瘤并计算。对于植入的肿瘤,通过体积=(长×宽2)/2或对于可诱导的肿瘤,通过体积=(长×宽×高)来计算肿瘤体积。为进行体内治疗,通过腹膜内注射,每三天向荷Yumm1.7小鼠施用DMSO或PPARβ激动剂(GW 501516)(每公斤体重1mg,Cayman Chemical)。对于基于抗体的处理,通过腹膜内注射根据指定的组合将荷瘤小鼠用抗PD-1抗体(每次注射200μg,BioXcell,克隆29F.1A12)和抗CD36抗体(每次注射200μg,克隆CRF D-2712(Driscoll,W.S.,et al.Circulation research 113,52-61(2013))处理。对于Braf/Pten小鼠模型中的抗体处理,在诱导肿瘤后四周,荷瘤的Braf/Pten小鼠为用上述指定的抗CD36抗体和/或抗PD-1抗体处理10天时间。所有实验均根据瑞士联邦法规进行。
肿瘤消化和细胞分离。在含有2%FBS、1%青霉素-链霉素(p/s)、DNase I(1μg/ml,Sigma-Aldrich)和胶原酶(0.5mg/ml,Sigma-Aldrich)的RPMI中将肿瘤切成小块,保持在37℃下消化40分钟,然后用70μm的细胞过滤器过滤。过滤后的细胞与ACK裂解缓冲液(Invitrogen)温育以裂解红细胞,然后用荧光激活细胞分选(FACS)缓冲液(磷酸盐缓冲液,含2%胎牛血清和2mM EDTA)洗涤。如前所述,在室温下通过percoll密度梯度离心(800x g,30分钟)进一步富集肿瘤浸润的白细胞(Cheng,W.C.et al.Nat Immunol 20,206-217(2019))。
流式细胞仪、细胞分选和抗体。在染色前,将单细胞悬液与Fc受体阻断性抗CD16/32(93)和抗CD351(TX61)抗体(Biolegend)在冰上温育10分钟。首先将细胞悬浮液用LIV/Fixable Violet死细胞染色试剂盒(ThermoFisher)在37℃下染色10分钟。洗涤后,将表面蛋白在4℃染色30分钟。为了检测离体再刺激后细胞因子的产生,将细胞悬浮液重新悬浮在具有10%FBS的RPMI 1640中,然后在存在2.5μg/ml布雷菲德菌素(Brefeldin)A溶液(BFA)(Biolegend)的条件下,加入到包被有1μg/ml抗CD3抗体(克隆145-2C11,Biolegend)和抗CD28抗体(克隆37.51,Biolegend)的平板中在37℃再放置5h。如上所述,对细胞进行表面标志物染色,然后进行细胞内细胞因子染色。在LSRII流式细胞仪(BD Biosciences)上分析样品,并使用FlowJo分析数据。在FACSAriaTMIII分选仪(BD Biosciences)或SH800S细胞分选仪(Sony)上分选细胞。使用针对小鼠蛋白质的以下抗体:抗CD45(30-F11)、抗CD3ε(17A2)、抗CD4(RM4-5)、抗CD8a(53.6.7)、抗CD44(IM7)、抗62L(Mel-14)、抗PD1(RMP1-30)、抗CD134(OX40)(OX-86)、抗CD357(GITR)(DTA-1)、抗CD36(CRF D-2712)、抗IgA(mA-6E1)、抗FoxP3(MF-14)、抗IFN-γ(XMG1.2)、抗TNF-α(MP6-XT22)、抗IL17A(TC11-18H10.1)、抗Ki67(16A8)、抗CD278(ICOS)(15F9)、抗CD152(CTLA4)(UC10-4B9)、切割胱天蛋白酶-3(Asp175)。这些抗体购自Biolegend、eBiosciences和Cell Signaling。
线粒体,脂肪酸摄取和脂质含量测定。为了测量线粒体膜电位,将细胞洗涤并与预热(37℃)染色溶液(含2%FBS的RPMI)一起温育15min,该染色溶液含有DeepRed FM(ThermoFisher)和Green FM(ThermoFisher),工作浓度分别为10nm和100nM。染色后,将细胞洗涤并重悬于新鲜的FACS缓冲液中,如上所述进行表面标志物染色。为了测量脂肪酸摄取,将细胞在含终浓度0.5μM的500/510C12(LifeTechnologies)的RPMI培养基(或人T细胞培养基)中于37℃温育15分钟。温育后,将细胞用FACS缓冲液洗涤以进行表面染色。对于脂质含量检测,透化和固定后,使用以终浓度500ng/ml的493/503(Life Technologies)和其他细胞内蛋白一起对细胞染色。
RNA测序和生物信息学分析。通过FACS细胞分选仪(具有至少99%纯度)将来自FoxP3YFP-Cre或TregCD36-/-小鼠的500-600个活的CD4+/CD44+/YFP+肿瘤内Treg直接分离到4μl裂解缓冲液中,所述裂解缓冲液由0.2%(体积/体积)Triton X-100溶液(MgBCH-Axon Lab)和RNase抑制剂(Clontech)组成。将含有样品的板密封,快速冷冻并保持在-80℃,然后按照之前描述的Smart-Seq2实验方案版本进行进一步处理(Picelli,S.et al.Natureprotocols 9,171-181(2014))。通过标准RNA-seq分析管线(pipeline)处理RNA测序原始数据。简要地,使用tophat2 v2.1.0检查了读段(read)比对,然后将其与小家鼠GRCm38.p4基因组版本进行比较。比对后,使用HTseq计数注释映射到每个基因的读段。基于DESeq2 R文库进行差异表达分析。然后通过基于START Web的RNA-seq分析资源(Nelson,J.W.,etal.Bioinformatics 33,447-449(2017).)检查差异表达测定并可视化。使用GSEA软件进行基因集富集分析(GSEA)。
电子显微镜分析和组织学分析。为了进行电子显微镜分析,将分选的细胞在4℃的戊二醛2.5%(EMS)和四氧化锇1%(EMS)中固定过夜,然后用水和丙酮(Sigma)洗涤几次,并在第二天包埋在Epon(Sigma)树脂中。成像前,使用Leica Ultracut切片机制备50nm载玻片,并使用醋酸铀(uranyl acetate)(Sigma)和雷诺兹柠檬酸铅(Reynolds lead citrate)(Sigma)进行对比。电子显微镜图像是利用透射电子显微镜Philips CM100以80kV的加速度和TVIPS TemCam-F416数码相机以4800x和11'000x的放大倍数拍摄的。图像分析和量化使用EMMENU,3dmod(科罗拉多大学)和Fifi(ImageJ)软件进行。为了量化每个分选细胞的线粒体,应用网格并将每个交叉点定义为细胞核、细胞质或线粒体的一部分,并测量每个嵴的长度除以线粒体面积,以确定嵴密度。为了进行组织学分析,修剪器官并将其放置在标记的盒中,并在福尔马林中固定24小时,以进一步包埋在熔融的石蜡中。根据标准程序,用苏木精和曙红对厚度为3-5μm的石蜡切片进行染色。拍摄图像并在Nikon Eclipse Ti-S倒置显微镜上输出。
人类患者评估。根据批准的方案,按照人类样品的伦理法规进行了此项研究。按照安全法规对人类样品进行分析,并用以下抗体进行FACS分析染色:抗CD45(2D1)、抗CD3(SK7)、抗CD4(SK3)、抗CD25(BC96)、抗CD8(RPA-TP)、抗CD36(TR9)、抗PD1(E12.1)和抗FoxP3(150D)。
结肠炎的T细胞转移模型。从FoxP3YFP-Cre小鼠或TregCD36-/-小鼠的脾脏中分选WT和CD36-KO Treg,并使用负磁选择(MojoSort小鼠CD4 T细胞分离试剂盒,Biolegend)和FACS分选组合收集幼稚CD4+T细胞(>98%纯度)。为了诱发结肠炎,将幼稚CD4+细胞(5×105个细胞)静脉内转移到Rag1-/-接受者中。在一些接受者中,将从FoxP3YFP-Cre小鼠或TregCD36-/-小鼠的脾细胞中分离得到的4×105个CD44+/YFP+Treg与幼稚CD4+T细胞共转移。转移后每两或三天对受体小鼠监测并称重,监测是否有疾病迹象,例如体重减轻。疾病发作通常发生在转移后4-5周。这项研究的终点包括确定体重减轻,结肠炎时间长短和腹泻。此外,收集结肠和小肠并进行处理,以通过苏木精和曙红染色进行进一步评估。
NAD和NADH测量。烟酰胺腺嘌呤二核苷酸(NAD)和烟酰胺腺嘌呤二核苷酸水合物(NADH)的比例是通过使用商用NAD/NADH定量试剂盒(Sigma-Aldrich MAK037)测量的。首先将细胞脱蛋白,以防止酶消耗NAD和NADH。用冷PBS洗涤后,将悬浮在NADH/NAD提取缓冲液(200μl)中的细胞团进行两次重复的冻融循环处理,然后在4℃下以13,000xg离心5分钟。然后将上清液分为两等份,一份用于NAD总检测,另一份在60℃加热30分钟以进行NAD分解。然后将样品转移到96孔板中以测量450nm的吸光度。表示的氧化的NAD(NAD+)的量从NAD总中减去NADH。样品中NAD/NADH的比例可以通过以下公式确定:比例=(NAD总–NADH)/NADH。
Seahorse细胞外流量(flux)分析。如前所述,利用XF96 Seahorse细胞外流量分析仪进行细胞外流量分析,并进行了一些修改(Liu,P.S.et al.Nat Immunol 18,985-994(2017))。细胞用寡霉素(0.5μM,Sigma-Aldrich)、FCCP(2μM,Sigma-Aldrich)、鱼藤酮(rotenone)(0.5μM,Sigma-Aldrich)、抗霉素A(0.5μM,Sigma-Aldrich)、葡萄糖(10mM,Sigma-Aldrich)和2-DG(50mM,Sigma-Aldrich)处理。每个条件在每个单独实验中进行3-6个重复。
统计分析。统计分析是使用双尾未配对的学生t检验进行的。对数秩(Mantel-Cox)检验用于存活曲线分析。每个点代表生物学上的重复,且所有数据均以平均值±SD,或平均值±SEM表示。P值表示如下:***P<0.001,**P<0.01和*P<0.05,P<0.05被认为具有统计学意义。
数据可用性。肿瘤内Treg的RNA-seq数据可在Gene Expression Omnibus数据库中获得。
实施例2:肿瘤内Treg增加脂质代谢和CD36表达
为了阐明肿瘤内Treg是否优先参与特定的代谢途径,在先前发表的研究中,首先分析了获自乳腺癌患者的肿瘤内Treg和循环Treg的RNA测序结果(Plitas,G.etal.Immunity 45,1122-1134)。基因途径分析,尤其着重于代谢途径,揭示与循环中的Treg相比,肿瘤内Treg高表达负责脂质代谢的代谢基因(图1a和1b),这表明肿瘤内Treg可能会增加其脂质代谢。确实,来自非小细胞肺癌(NSCLC)患者的外周血单核细胞(PBMC)与肿瘤内Treg之间的比较显示,肿瘤内Treg内化了更高量的绿色荧光脂肪酸,Bodipy FL C12,并且含有更高的基于Bodipy染色的中性脂质含量。为了进一步探索这些表型,使用黑色素瘤细胞植入模型评估位于肿瘤和其他周围组织中的Treg的脂质代谢。结果表明,与来自荷YUMM1.7黑色素瘤的小鼠的其他组织的Treg相比,肿瘤内Treg表现出更高的摄取脂肪酸的能力(图1c)和具有更高的脂质含量(图1c)。同样,荷B16黑色素瘤小鼠的肿瘤内Treg也表现出增强的脂肪酸摄取。这些观察结果表明,在人和鼠模型中,肿瘤内Treg引起的脂质代谢的增加是保守的表型。值得注意的是,在控制脂质摄取的基因中,负责长链脂肪酸和氧化的低密度脂蛋白摄取的清道夫(scavenger)受体CD36与来自乳腺癌患者的循环Treg相比,在肿瘤内Treg中显著上调(Plitas,G.et al.Immunity 45,1122-1134)。通过检查来自黑色素瘤患者的PBMC和肿瘤浸润淋巴结(TILN)中的Treg,证实大多数患者的肿瘤内Treg表达更高水平的CD36(图1e)。此外,肿瘤内的Treg,而不是来自荷Yumm1.7黑色素瘤小鼠的其他周围组织或次级淋巴器官中的Treg,表达高水平的CD36(图1f)。值得注意的是,在B16黑色素瘤模型中,基因工程Braf/PTEN黑色素瘤小鼠模型和NSCLC的K-rasLSL-G12D/+/p53fl/fl条件小鼠模型中,也观察到了在肿瘤内Treg中发现的CD36表达增加。此外,在条件培养基中培养的获自癌细胞培养物的诱导型Treg(iTreg)大大增加了CD36的表达,而低氧和乳酸则不能诱导Treg中CD36的表达。值得注意的是,脂质去除消除了癌细胞条件培养基对Treg中CD36表达的刺激作用。总之,结果表明TME可以刺激Treg中CD36表达,这可以支持肿瘤内Treg对代谢适应的需求。
实施例3:CD36控制肿瘤内Treg的积累并抑制功能
为了研究CD36的表达是否调节肿瘤中的Treg行为,通过使CD36fl/fl小鼠与Foxp3YFP-Cre小鼠杂交,产生了Treg特异性CD36缺陷型小鼠(称为TregCD36-/-)。鉴于Treg中关键调节因子的遗传去除(ablation)可能会由于Treg抑制功能的损害而导致T淋巴细胞的系统活化和自身免疫,首先检查了Treg中CD36的缺乏是否会影响免疫稳态。发现在两种性别中,年老的TregCD36-/-小鼠(21-23周)显示出与Foxp3YFP-Cre小鼠(在整个研究中称为野生型小鼠)相当的体重。与WT小鼠相比,TregCD36-/-小鼠在CD4+和CD8+T细胞区室中也包含相似比例的效应子或记忆群体(CD44hiCD62Llo)。此外,TregCD36-/-小鼠既未显示出各种器官中淋巴细胞和髓样细胞的异常浸润,也未显示严重的系统性炎症性病症(图2a),表明Treg不需要CD36即可维持免疫稳态。
然后将YUMM1.7黑色素瘤细胞植入到WT和TregCD36-/-小鼠中。观察到Treg中CD36的遗传去除显著降低了肿瘤内Treg的脂质摄取和含量,但脾脏Treg却没有(图2b和2c),表明肿瘤内Treg依赖CD36的表达来支持增加的脂质摄取。在TregCD36-/-小鼠中还观察到植入的YUMM1.7黑色素瘤(图2d和2e)、B16黑色素瘤和MC38结肠癌的生长减速。此外,在分析终点时,在TregCD36-/-小鼠具有显著下降的肿瘤内Treg,但脾脏和引流淋巴结中的Treg却没有(图2f)。这伴随着CD8+TIL频率的显著增加以及CD8+与Treg TIL的比率增加,这是与强抗肿瘤响应相关的有利参数。此外,TregCD36-/-小鼠中较高频率的CD8+TIL和CD4+/FoxP3-TIL产生抗肿瘤效应细胞因子,包括干扰素-γ(IFNγ和肿瘤坏死因子-α(TNFα)(图2g),这表明TregCD36-/-小鼠的TME的免疫抑制力较低。
为了进一步验证CD36对支持肿瘤内Treg积累的依赖性,产生了杂合型Foxp3YFP -Cre/+/CD36fl/fl雌性小鼠,其同时含有WT Treg群体和X染色体失活介导的FoxP3表达驱动的CD36敲除Treg群体。WT和CD36缺陷型Treg可以基于黄色荧光蛋白(YFP)的表达进行检测。为了排除由Cre重组酶诱导的潜在毒性,还产生了杂合的Foxp3YFP-Cre/+雌性小鼠作为对照小鼠。通过比较荷瘤Foxp3YFP-Cre/+/CD36fl/fl和Foxp3YFP-Cre/+雌性小鼠的FoxP3+Treg中的YFP+群体,仅检测到肿瘤中CD36缺陷型Treg的频率降低(Foxp3YFP-Cre/+/CD36fl/fl小鼠中的Cre+群体),而脾脏和引流淋巴结中Cre+和Cre-Treg之间的频率比Foxp3YFP-Cre/+/CD36fl/fl和Foxp3YFP-Cre/+小鼠之间相当。该结果表明,CD36表达的丧失通过内在调控选择性地干扰了肿瘤内Treg的积累。总之,这些结果揭示了CD36在选择性赋予Treg具有在TME中积累的能力中的关键作用。
实施例4:CD36在Treg用于维持外周稳态中是非必要的
有趣的是,还发现在鼠黑色素瘤模型中,与肿瘤内CD44lo Treg(静息Treg)相比,肿瘤内效应Treg(CD44hi/CD62Llo)表达了更高水平的CD36。类似地,与来自黑色素瘤患者和健康供体的PBMC中的GITR+/CD25+效应Treg相比,来自黑色素瘤患者的TIL中肿瘤浸润GITR+/CD25+效应Treg(效应Treg的最强抑制性子集)以较高百分比表达CD36。还检查了肿瘤内Treg中免疫调节受体的表达。发现与WT Treg相比,CD36-KO Treg降低了糖皮质激素诱导的TNFR相关蛋白(GITR)和OX40的表达,但未降低程序性细胞死亡蛋白1(PD-1)、CD25、细胞毒性T淋巴细胞相关蛋白4(CTLA-4)或诱导性T细胞共刺激物(ICOS)。这些结果表明CD36表达有助于效应Treg的抑制功能。为了支持该观点,在体外抑制测定中,与WT肿瘤内Treg相比,来自TregCD36-/-小鼠的肿瘤内Treg显示出降低的抑制能力(图2h)。但是,WT和CD36缺陷型脾脏Treg表现出相当的抑制能力(图2i),表明CD36仅是支持肿瘤内Treg抑制活性所必需的,但在脾脏Treg中不是必需的。
为了进一步检查CD36是否可用于Treg抑制外周炎症,分析了CD36缺陷Treg抑制T细胞转移诱导的结肠炎的能力。在幼稚CD4+T细胞转移后两周检测到疾病发作,例如体重减轻。但是,与WT Treg相比,共转移CD36-KO Treg能够改善受体小鼠的体重减轻(图2j)。此外,在研究终点去除了几个器官,并进行了处理以通过组织学进一步评估。与幼稚CD4+T细胞转移引发淋巴细胞和髓样细胞大量浸润相比,WT或CD36-KO Treg的共转移会阻碍淋巴细胞和髓样细胞浸润以及结肠和小肠的形态变化,结肠缩短,且受体小鼠脾脏肿大。此外,发现肿瘤内Treg中CD36的遗传去除既不影响活化标志物(包括CD44、CD103和KLRG1)的表达,也不影响FoxP3表达(由YFP的荧光强度指示)。但是,缺乏CD36的肿瘤内Treg会稍微提高促炎细胞因子IFNγ和TNF的产生,表明CD36限制了在肿瘤内Treg中产生促炎细胞因子的能力。总之,结果表明CD36表达明确支持肿瘤内Treg抑制功能。
实施例5:CD36缺乏刺激肿瘤内Treg的凋亡
为了研究TME中CD36缺陷型Treg减少细胞结构的潜在基础,首先通过对Ki67染色来检查其增殖能力。发现CD36缺陷型并没有改变肿瘤内Treg的增殖。WT和CD36缺陷型肿瘤内Treg的转录组的比较显示CD36缺陷型Treg展示出控制细胞凋亡的基因升高的表达(图3a)。实际上,在CD36缺陷型的肿瘤内Treg中观察到了较高水平的切割的胱天蛋白酶-3(图3b)和膜联蛋白V染色(图4h)。值得注意的是,CD36缺陷型并没有增强来自胸腺和其他继发性淋巴样器官的Treg中切割的胱天蛋白酶-3水平,除了在引流淋巴结略有增加,表明肿瘤内Treg需要CD36介导的调节以防止凋亡。
由于已经提出线粒体代谢和适应性以调节Treg抑制功能和存活(Yang,K.etal.Nature 548,602-606(2017);Weinberg,S.E.et al.Nature 565,495-499(2019);He,N.et al.PNAS 114,12542-12547(2017);Beier,U.H.et al.FASEB J29,2315-2326(2015)),然后检查CD36缺陷型肿瘤内Treg是否不能维持线粒体适应性。令人惊讶的是,正如通过MitoTracker DeepRed染色测量的,与WT Treg相比,CD36缺陷型肿瘤内Treg而非其他组织的Treg展示出降低的线粒体膜电位(Fig.3c)。电子显微镜分析进一步支持了该观察结果,其显示来自TregCD36-/-小鼠的肿瘤内Treg具有较少的线粒体(图3d)以及每个线粒体中较少的嵴(cristae)(图3e)。然而,WT和CD36缺陷型脾脏Treg展示线粒体和嵴密度的相当数量。为了进一步阐明CD36对Treg线粒体代谢的影响,如上所示,将从WT或CD36缺陷型CD4+T细胞产生的iTreg用癌细胞条件培养基处理以诱导CD36表达。进行了Seahorse细胞外流量(flux)测定。如图3f所示,CD36缺陷型Treg表现出降低的耗氧率(OCR)但增加了糖分解速率。这些结果表明,CD36去除可损害氧化磷酸化(OXPHOS),并使Treg的代谢偏好趋向有氧糖酵解。这些观察结果表明,肿瘤内Treg中增强CD36表达可能通过调节线粒体适应性来响应TME施加的代谢胁迫,从而支持Treg代谢的灵活性(Li,X.et al.Nat Rev Clin Oncol(2019);Ho,P.C.et al.Cell162,1217-1228(2015);Siska,P.J.&Rathmell,J.C.TrendsImmunol 36,257-264(2015))。
还检查了CD36缺陷型Treg是否展示出对代谢挑战的存活缺陷。与正常培养条件(RMPI加10%FBS;指定为RMPI)相比,暴露于癌细胞条件培养基的CD36缺陷型Treg的活力降低。由于在癌细胞条件培养基中乳酸水平会增加,而乳酸的积累是TME的普遍特征,因此假设CD36缺陷型Treg可能由于高含量的乳酸而无法在这种情况下维持存活。为了支持这种假设,发现CD36缺陷型Treg对乳酸逐步上升的剂量展示出严重的存活缺陷(图3g)。与此结果相符的是,最近的研究表明,提高的电子传输链活性导致增加的NAD/NADH比例,以支持Treg中乳酸转化为丙酮酸(Angelin,A.et al.Cell Metab 25,1282-1293e1287(2017)),其可以在富含乳酸的条件下支持Treg的存活。因此,设想由于降低的线粒体适应性和OXPHOS,与WTTreg相比,CD36缺陷型Treg可能具有较低的NAD/NADH比率。实际上,如图3h所示,与WT Treg相比,CD36缺陷型Treg具有较低的NAD/NADH比率,添加烟酰胺核糖(NR)以补充NAD可以部分挽救暴露于癌细胞条件培养基的CD36缺陷型Treg的活力(Fig.3i)。因此,CD36缺陷型肿瘤内Treg不能在体内持续存在可能是由于线粒体适应性和OXPHOS降低,这使得Treg可以通过NAD调节的代谢过程在富含乳酸的条件下存活。
实施例6:CD36-PPARβ信号转导指导肿瘤内Treg的新陈代谢适应
为了了解CD36如何刺激肿瘤内Treg的线粒体适应性,评估了来自乳腺癌患者肿瘤内和循环Treg转录组的变化。不出所料,肿瘤内Treg上调了控制线粒体功能和生物发生的基因。此外,发现肿瘤内Treg展示参与PPAR信号途径的基因表达增加(图4a)。由于已经建议CD36通过增强PPARβ-(PPARβ也称为PPARβ)和PPARγ依赖性的线粒体活性和生物发生调节来支持代谢组织的代谢灵活性,因此CD36诱导的代谢重编程可能通过提供脂质信号来促进肿瘤内Treg线粒体适应性以调节PPAR转录调控。为了检验这一概念,将PPARβfl/fl和PPARγfl/fl小鼠分别与Foxp3YFP-Cre小鼠杂交以获得Treg特异性PPARβ-缺陷型小鼠(指定为TregPPARβ-/-)和PPARγ-缺陷型小鼠(指定为TregPPARγ-/-)。观察到,Treg中PPARγ的遗传去除既不损害肿瘤内Treg的积累也不损害YUMM1.7黑色素瘤的生长。相反,TregPPARβ-/-小鼠概括了TregCD36-/-小鼠的特征,包括降低的肿瘤内Treg积累(图4b),植入的YUMM1.7黑色素瘤的生长减慢(图4c和4d),以及CD8+的增加。与CD36缺陷型肿瘤内Treg相似,PPARβ缺陷型肿瘤内Treg与WT肿瘤型Treg相比,展示降低的线粒体膜电位(图4e)。值得注意的是,与WT肿瘤内Treg相比,PPARβ缺陷型肿瘤内Treg表达更少的CD36。考虑到脂质去除消除了癌细胞条件培养基诱导Treg中CD36表达的能力,结果进一步表明脂质诱导的PPARβ信号可能有助于肿瘤内Treg中CD36诱导。
为了阐明CD36和PPARβ活化及其在支持肿瘤内Treg积累中的作用之间的关系,将YUMM1.7黑色素瘤植入的WT小鼠和TregCD36-/-小鼠用PPARβ选择性激动剂(GW501516)或对照媒介物处理两周。如图4f和4g所示,用GW501516处理恢复了TregCD36-/-小鼠中的肿瘤生长以及肿瘤内Treg的丰度(图4f和4g)。另外,来自GW501516处理的TregCD36-/-小鼠的肿瘤内Treg具有增加的线粒体膜电位和较低水平的切割的胱天蛋白酶-3(图4h和4i)。同时,在CD36缺陷型Treg中GW501516处理增加NAD/NADH比率,表明CD36控制的脂质摄取激活PPARβ途径,以支持肿瘤内Treg中线粒体适应性和提高的NAD/NADH比率。而且,PPARβ途径的激活可以通过增强CD36表达来进一步放大肿瘤内Treg中CD36介导的代谢适应。总而言之,这些结果揭示CD36-PPARβ信号转导协调代谢程序以支持TME中的Treg持久性。
实施例7:通过损害肿瘤内Treg靶向CD36增强抗肿瘤免疫力
接下来,研究了阻断CD36介导的代谢适应是否能特异性干扰肿瘤内Treg而没有Treg的系统性损失和Treg抑制功能的全面损害。用抗CD36单克隆抗体(mAb)处理植入Yumm1.7黑色素瘤的小鼠,该抗体会干扰CD36介导的脂肪酸和氧化的低密度脂蛋白摄取。如图5a所示,抗CD36 mAb处理降低了肿瘤的生长,并伴有肿瘤内Treg的降低的积累,而Treg群体在脾脏和引流淋巴结中得以维持(图5b和6a)。与Treg中CD36的遗传去除相似,抗CD36mAb处理促进肿瘤内Treg中的细胞凋亡(图5c),并导致CD8+T细胞的肿瘤浸润显著增加(图6b)。另外,用抗CD36 mAb处理小鼠改善了CD8+和CD4+TIL中抗肿瘤效应细胞因子的产生(图6c和6d)。由于CD36表达可以支持癌细胞以及其他免疫细胞的代谢灵活性和转移,因此抗CD36 mAb诱导的抗肿瘤响应可能是独立于Treg。为了检验该概念,使用TregCD36-/-小鼠进行与接受者相同的处理。结果表明,抗CD36 mAb处理无法抑制TregCD36-/-小鼠的肿瘤进展(图5d),表明抗CD36 mAb处理诱导的抗肿瘤响应可能主要由靶向Treg中表达的CD36引起,而不是其他表达CD36的细胞。
由于T细胞耗竭可能会限制靶向Treg的干预的治疗效果,因此用PD-1阻断来恢复耗尽的T细胞可能会增强CD36阻断的抗肿瘤作用,以抑制肿瘤的进展。实际上,与WT小鼠相比,抗PD-1mAb在荷瘤的TregCD36-/-小鼠中更有效地限制了肿瘤的进展和延长存活(图5e和5f)。除了遗传去除Treg中的CD36外,抗PD-1mAb还在遗传改造的Braf/PTEN黑色素瘤小鼠模型(图5g)和YUMM1.7植入模型(图5h)中均增强了抗CD36 mAb的抗肿瘤响应。这些结果表明,在Treg中靶向CD36可能会使TME重新编程,使其适应更多的免疫刺激条件,这可能在治疗上补充了PD-1阻断作用以抵消T细胞耗竭。这表明CD36阻断作为一种新的潜在的免疫治疗干预措施,具有由Treg的全身性损伤引起的减少的副作用。
在图7a-f中进一步证明了检查点阻断抑制剂(例如,PD1和CTLA4抑制剂)的协同作用。对于肿瘤植入,将50μl PBS中的5×104个细胞YUMM1.7肿瘤细胞皮下注射。肿瘤植入后每隔2~3天测量肿瘤或进行指定处理并计算。通过体积=(长×宽2)/2来计算肿瘤体积。对于基于抗体的处理,根据腹膜内注射的指示组合,将荷瘤小鼠用抗PD-1抗体(每次注射200μg,BioXcell,克隆29F.1A12)、抗CTLA4抗体(每次注射200μg,BioXcell,克隆9D9)和抗CD36抗体(每次注射200μg,克隆CRF D-2712)处理。
如图7a、7c、7d和7e所示,用抗CD36单克隆抗体(mAb)和抗CTLA4 mAb处理植入Yumm1.7黑色素瘤的小鼠。发现抗CD36 mAb处理降低了肿瘤的生长,并伴随着肿瘤内Treg频率降低,而Treg群体在脾和引流淋巴结中得以维持,这是通过抗CTLA4 mAb处理无法实现的。另外,类似于图5h所示结果,抗PD-1mAb还可增强YUMM1.7植入模型中抗CD36 mAb的抗肿瘤响应,尽管抗PD-1mAb和抗CTLA4 mAb的组合处理也降低了肿瘤生长。这些结果表明在Treg中靶向CD36可能会使TME重新编程,使其适应更多的免疫刺激条件,这可能在治疗上对应PD-1阻断作用以抵消肿瘤进展。
本公开中呈现的结果表明,肿瘤内Treg上调CD36的表达以促进脂肪酸摄取。内在的脂肪酸通过激活控制线粒体生物发生和功能的PPARβ介导的转录程序,进一步支持线粒体适应性。表达CD36的肿瘤内Treg中增强的线粒体适应性导致NAD通过电子传输链复合物I再生,继而维持乳酸→丙酮酸转化。作为通过NAD再生持续支持乳酸→丙酮酸转化的结果,肿瘤内Treg可以在酸性肿瘤微环境中存活,并且可以利用乳酸衍生的丙酮酸来支持免疫抑制活性。
利用调节回路(circuit)(通过其代谢过程协调了免疫细胞中的免疫响应)是微调宿主疾病免疫力的一种有吸引力的策略。本公开证明CD36-PPARβ信号转导通过调节线粒体适应性和NAD水平来维持肿瘤内Treg中的存活和功能适应性。由于在TME中发生的代谢胁迫的独特性以及肿瘤内Treg的CD36-PPARβ信号转导的选择性,靶向CD36可以提供广泛的治疗潜力,对癌症患者的免疫和周围组织动态平衡具有有限的负面影响。而且,通过用PD-1阻断剂和CD36靶向联合治疗引起的累积抗肿瘤作用进一步保证了CD36抑制方法发展为潜在的癌症治疗。
根据本公开,可以在没有过度实验的情况下进行和执行本文公开和要求保护的所有方法和设备。尽管已经根据优选实施方案描述了本发明,但对于本领域的普通技术人员将显而易见的是,在不脱离本发明的概念、精神和范围的情况下,可以将各种变型应用于该方法的装置、方法和步骤顺序中。更具体地,将显而易见的是,可以将某些组分添加、组合或代替本文描述的组分,同时将获得相同或相似的结果。对于本领域普通技术人员显而易见的所有此类类似的替代和修改都被认为在所定义的本发明的精神、范围和概念内。
Claims (33)
1.在有需要的受试者中降低肿瘤内调节性T细胞的数量的方法,其包括向所述受试者施用有效量的CD36抑制剂。
2.在有需要的受试者中降低肿瘤内调节性T细胞的数量的方法,其包括向所述受试者施用有效量的PPARβ抑制剂。
3.权利要求1或2的方法,其中所述肿瘤内调节性T细胞是CD4+细胞。
4.在有需要的受试者中增加肿瘤内细胞毒性T细胞的数量的方法,其包括向所述受试者施用有效量的CD36抑制剂。
5.在有需要的受试者中增加肿瘤内细胞毒性T细胞的数量的方法,其包括向所述受试者施用有效量的PPARβ抑制剂。
6.权利要求4或5的方法,其中所述肿瘤内细胞毒性T细胞是CD8+细胞。
7.权利要求1或4的方法,其中所述CD36抑制剂是抗CD36抗体或小分子CD36抑制剂。
8.权利要求7的方法,其中所述抗CD36抗体是人抗体、人源化抗体、嵌合抗体或双特异性抗体。
9.权利要求7的方法,其中所述小分子CD36抑制剂选自下组:AP-5258、AP5055、EP-80317、MPE-002、CHEML1789142、CHEML1789302、CHEML1789297、CHEML1789141、CHEML1789270、CHEML1789308。
10.权利要求1、4和7-9中任一项的方法,其中所述CD36抑制剂以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
11.权利要求2或5的方法,其中所述PPARβ抑制剂是抗PPARβ抗体或小分子PPARβ抑制剂。
12.权利要求11的方法,其中所述抗PPARβ抗体是人抗体、人源化抗体、嵌合抗体或双特异性抗体。
13.权利要求11的方法,其中所述小分子PPARβ抑制剂选自下组:FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
14.权利要求2、5和11-13中任一项的方法,其中所述PPARβ抑制剂以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
15.前述权利要求中任一项的方法,进一步包括向所述受试者施用额外的治疗剂。
16.权利要求15的方法,其中所述额外的治疗剂包含免疫检查点调控剂。
17.权利要求16的方法,其中所述免疫检查点调控剂包含对以下具有特异性的抗体:CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。
18.权利要求15的方法,其中所述额外的治疗剂包含抗PD-1单克隆抗体、抗CTLA4单克隆抗体,或其组合。
19.前述权利要求中任一项的方法,其中所述受试者患有癌症。
20.权利要求19的方法,其中所述癌症选自下组:口腔癌、口咽癌、鼻咽癌、呼吸道癌、泌尿生殖道癌、胃肠道癌、中枢或周围神经系统组织癌、内分泌或神经内分泌癌或造血癌、神经胶质瘤、肉瘤、癌瘤(carcinoma)、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺瘤、成骨肉瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头和颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌和皮肤癌。
21.在患有癌症的受试者中抑制肿瘤生长的方法,其包括向所述受试者单独或与额外的治疗剂组合施用治疗有效量的CD36抑制剂。
22.在患有癌症的受试者中抑制肿瘤生长的方法,其包括向所述受试者单独或与额外的治疗剂组合施用治疗有效量的PPARβ抑制剂。
23.权利要求21的方法,其中所述CD36抑制剂是抗CD36抗体或小分子CD36抑制剂。
24.权利要求23的方法,其中所述抗CD36抗体是人抗体、人源化抗体、嵌合抗体或双特异性抗体。
25.权利要求23的方法,其中所述小分子CD36抑制剂选自下组:AP-5258、AP5055、EP-80317、MPE-002、CHEML1789142、CHEML1789302、CHEML1789297、CHEML1789141、CHEML1789270、CHEML1789308。
26.权利要求21和23至25中任一项的方法,其中所述CD36抑制剂以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
27.权利要求22的方法,其中所述PPARβ抑制剂是抗PPARβ抗体或小分子PPARβ抑制剂。
28.权利要求27的方法,其中所述抗PPARβ抗体是人抗体、人源化抗体、嵌合抗体或双特异性抗体。
29.权利要求27的方法,其中所述小分子PPARβ抑制剂选自下组:FH535、GSK0660、GSK3787、PT-S58、PT-S77和ST-247。
30.权利要求22和27至30中任一项的方法,其中所述CD3抑制剂以肿瘤内、静脉内、皮下、骨内、口服、透皮、以持续释放、受控释放、延迟释放的形式,作为栓剂或舌下施用。
31.权利要求21至30中任一项的方法,其中所述额外的治疗剂包含免疫检查点调控剂。
32.权利要求31的方法,其中所述免疫检查点调控剂包含特异性的抗体,例如对以下具有特异性的抗体:CTLA-4、PD-1、PD-L1、PD-L2、杀伤性免疫球蛋白受体(KIR)、LAG3、B7-H3、B7-H4、TIM3、A2aR、CD40L、CD27、OX40、4-IBB、TCR、BTLA、ICOS、CD28、CD80、CD86、ICOS-L、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40和GALS。
33.权利要求21至32中任一项的方法,其中所述癌症选自下组:口腔癌、口咽癌、鼻咽癌、呼吸道癌、泌尿生殖道癌、胃肠道癌、中枢或周围神经系统组织癌、内分泌或神经内分泌癌或造血癌、神经胶质瘤、肉瘤、癌瘤(carcinoma)、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺瘤、成骨肉瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头和颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌和皮肤癌。
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