JP2019518452A - 腫瘍浸潤制御性t細胞において選択的に脱制御されたマーカー - Google Patents
腫瘍浸潤制御性t細胞において選択的に脱制御されたマーカー Download PDFInfo
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Abstract
Description
a) 抗体又はそのフラグメント;
b) ポリペプチド;
c) 小分子;
d) 上記の抗体又はポリペプチドをコードするポリヌクレオチド又はそれらの機能的誘導体;
e) ポリヌクレオチド、例えばアンチセンス構築物、アンチセンスオリゴヌクレオチド、RNA干渉構築物又はsiRNA,
e) d)又はe)において定義されるポリヌクレオチドを含む又は発現するベクター;
f) 上記のポリペプチド若しくは抗体を発現する又はd)若しくはe)において定義されるポリヌクレオチドを含む、遺伝子的に組み換えられた宿主細胞。
における腫瘍の治療的処置をスクリーニングする為のイン・ビトロ方法であって、
a) 上記対象者から得られた単離された生物学的サンプルにおいて、上記に定義されたマーカーの少なくとも1つを検出すること、そして
b) 適切な対照と比較すること
の工程を含む、上記方法である。
a) 上記対象者から得られた単離された生物学的サンプルにおいて、LAYN、MAGEH1及びCCR8からなる群から選択される少なくとも1つのマーカーを検出すること、そして
b) 適切な対照と比較すること
の工程を含み、
対象者から得られた単離された生物学的サンプル中の上記少なくとも1つのマーカーの、対照量よりも高い量が、上記対象者が予後不良を有することを示す、上記方法である。
a )上記対象者から得られた上記単離された生物学的サンプルにおいて、上記マーカー若しくはそのフラグメントの量の変化若しくは活性の変化、又は上記タンパク質若しくはそのフラグメントをコードするポリヌクレオチドの量の変化若しくは活性の変化を測定すること、そして、
b) 工程a)の測定された変化を適切な対照変化
の工程を含む、上記方法を含む。
上記に定義された少なくとも1つのマーカーに対する候補分子の結合特異性について該候補分子をアッセイすること;
上記に定義された少なくとも1つのマーカーに対する特異的結合活性を有する分子を選択すること;
好ましくは腫瘍浸潤制御性T細胞を選択的に枯渇させることによって、より好ましくは抗体依存性の細胞介在性細胞傷害活性(ADCC)を誘発することによって、増殖を阻害する及び/又は細胞系においてアポトーシス応答を誘発する能力について該特異的結合分子を試験すること
の工程を含む、上記方法である。
上記マーカー若しくはそのフラグメントの量若しくは活性を測定する手段、及び/又は上記タンパク質若しくはそのフラグメントをコードするポリヌクレオチドの量を測定する手段、及び任意的に
制御手段
を含む、上記キットである。
上記化合物に特異的な固相接着した抗体と;
リガンド特異的マーカー複合体の検出手段と
を含む。
初代ヒト肺又は結腸直腸腫瘍及び非腫瘍性対応部分が、Fondazione IRCCS Ca’ Granda,Policlinico又はSan Gerardo Hospitals(イタリア)で治療目的の為の手術を受けた15人及び14人の患者からそれぞれ得られた。記録が、全ての場合について入手可能であり且つ診断での患者の年齢、性別、喫煙習慣(肺癌患者について)、臨床病理学的段階(Sobin等.,2009年)、腫瘍ヒストタイプ(histotype)及び等級(grade)が含まれていた(表II)。緩和手術又はネオアジュバント化学療法及び/又は放射線療法を受けた患者はいなかった。インフォームドコンセントが全ての患者から得られ、そして該研究は、Fondazione IRCCS Ca’ Grandaの機関審査委員会(Institutional Review Board)によって承認された(承認番号30/2014)。
表面マーカー発現を確認する為に、細胞が以下の蛍光色素で複合化された抗体で直接染色され、そしてフローサイトメトリーにより解析された:抗-CD4(Biolegend,クローンOKT4);抗-PD-L2(Biolegend,クローンCL24F.10C12);抗-CD127(eBioscience,クローンRDR5);抗-BATF(eBioscience,クローンMBM7C7)、抗-GITR(eBioscience,クローンeBIOAITR)、抗-CD25(Miltenyi,クローン4E3)及び抗4-1BB(eBioscience,クローン4B4)、抗CCR8(Biolegend,クローンL263G8)、抗CD30(eBioscience,クローンBer-H2)、抗PD-L1(Biolegend,クローン29E.2A3)、抗TIGIT(eBioscience,クローンMBSA43)、抗IL1R2(R and D,クローン34141)、IL21R(Biolegend,クローン2G1-K12)、抗OX40(Biolegend,クローンBer-ACT35)。細胞内染色が、製造者のプロトコル(eBioscience cat 00-5523-00)に従い、eBioscience Foxp3染色キットを用いて行われた。簡単に、細胞が収穫され、そして固定/透過化バッファー中で、30分間、4°Cで固定化され、そして次に、透過化バッファー中で、30分間、4°Cで、抗-FOXP3抗体(eBioscience,クローン236A/E7)及び抗-BATF(eBioscience,クローンMBM7C7)で染色された。次に、細胞が2回洗浄され、FACS洗浄バッファ中で再懸濁され、そしてフローサイトメトリーによって解析された。
健康なドナーからの、4×104のカルボキシフルオレセインジアセテートスクシンイミジルエステル(CFSE:carboxyfluorescein diacetate succinimidyl ester)で標識付けされた(1μM)レスポンダーナイーブ+T細胞が、CRC又はNSCLCを有する患者のTILs又はPBMCsから選別された、標識付けされていないCD127-CD25lowCD4+T細胞と、FACS Aria II(BD Biosciences)を用いて、抗原提示細胞としてのCD11c+CD1c+樹枝状細胞及び0.5mg/mlの抗-CD3(OKT3)mAbの存在下で共培養された。CFSEで標識付けされた細胞の増殖が、96時間培養後に、フローサイトメトリーによって評価された。
腫瘍浸潤のリンパ球由来のRNAが、mirVana Isolationキットを用いて単離された。残存する混入しているゲノムDNAが、Turbo DNA-free(Thermo Fisher)を用いて、全RNA画分から除去された。RNA収率が、QuantiFluor RNA System(Promega)を用いて定量され、且つRNA品質がAgilent 2100 Bioanalyzer(Agilent)によって評価された。Illumina配列決定の為のライブラリーが、Illumina TruSeq RNAサンプル調製物キット v2(セットA)を用いて50ngの全RNAから構築された。生成されたライブラリーは、HiSeq Flow cell v3上でクラスター化する為に、cBot(Illumina)上にロードされた。次に、フロー細胞が、高出力モードにおけるHiSeq 2500(Illumina)を用いて配列決定された。ペアーエンド(2×125)ランが実行された。
Raw.fastqファイルがFastQC v0.11.3を用いて解析され、及びアダプター除去がcutadapt 1.8を用いて実行された。Cutadaptは、デフォルト・パラメータ[--anywhere<adapter1>--anywhere<adapter2>--overlap10--times2--mask-adapter].で、逆方向配列と順方向配列の両方で実行される。ライブラリー調製に用いられるアダプター配列は、下記の通りである。
アダプター1:AGATCGGAAGAGCACACGTCTGAACTCCAGTCACNNNNNNATCTCGTATGCCGTCTTCTGCTTG(SEQ ID No:710)
アダプター2:AGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT(SEQ ID No:711)
上方制御された遺伝子/下方制御された遺伝子が、0.05FDRの閾値を超えることが見つけられた場合に(Benjamini-Hochberg correction)、それらの発現値がその後の解析のために選択される。
5つのCRC及び5つのNSCLC標本からのTreg細胞が、以前に記載された通り単離された(表IIをまた参照)。単一細胞が、C1系(Fluidigm)上のマイクロ流体チップ上で捕捉され、全トランスクリプトームが増幅された。cDNAが、SMARTer Ultra Low RNAキット(Clontech)を用いてチップ上で調製された。細胞が3-5E5細胞/mlの濃度でチップ上にロードされ、生存能力について染色され(生/死の細胞生存能力アッセイ;Thermo Fisher)、そして位相差顕微鏡及び蛍光顕微鏡によって画像化されて、捕捉部位当たりの細胞の数及び生存能力を評価した。単一の、そして生きている細胞のみが解析に含まれた。qPCR実験の為に、収穫されたcDNAが、qPCRの為に使用されるべき同じ遺伝子発現アッセイから調製されたプライマーの0.2Xプールを用いて予め増幅された。前増幅は、多重配列特異的増幅の為に78個の標的を許す。詳細には、1.25μlのアリコートの単一細胞cDNAが、1μlのPreAmp Master Mix(Fluidigm)及び1.25μlのプールされたTaqMan assay mix(0.2x)を用いて5μlの最終容量で前増幅された。cDNAが、95°Cで15秒間、変性し、そして60°C、4分間、20サイクルでのアニーリングにより増幅された。サイクルの後、前増幅されたcDNAが、20μlのTEバッファーを最終5μl反応容量に加えて総容量の25μlにすることによって1.5倍に希釈された。
RT-qPCR単一細胞実験において使用されるTaqManプローブ及びアッセイ番号のリスト。
統計分析が、R生存パッケージ(Therneau T.2013年)を用いることによって行われた。生存期間は、最初の病理学的診断から死亡までの日数、又は最初の病理学的診断から最後に患者が生きていると報告されるまでの日数として計算された。カプラン・マイヤー(KM)が、CRC(GSE17536)患者及びNSCLC(GSE41271)患者のいずれかにおいても腫瘍-Treg細胞署名転写物の高発現レベルと低発現レベルとを比較する為に用いられる。両方の研究について、注釈が、4つの腫瘍段階(1,2,3,4)に正規化された。GSE41271試験について、5人の患者が不完全な又は不正確な注釈である故に除外され(GSM1012883,GSM1012884,GSM1012885,GSM1013100,GSM1012888)、合計233人の患者が保持された。両方の研究からの患者は、それらの相対発現値が決定境界(サンプルの平均)を超えたか否かにかかわらず、「高」、「低」として標識付けされた。
本データの受託番号は下記の通りである:ENA:RNA-seqの腫瘍及び組織湿潤リンパ球の為のPRJEB11844;ArrayExpress:RNA-seqのヒトリンパ球データセットの為のE-MTAB-2319;ArrayExpress:Illumina Human BodyMap 2.0 projectの為のE-MTAB-513;GEO:RNA-seqのデータセットCRCの為のGSE50760;GEO:RNA-seqのデータセットNSCLCの為のGSE40419;GEO:アレイによるCRC発現プロファイリングの為のGSE17536;及びGEO:アレイによるNSCLC発現プロファイリングの為のGSE41271。
関心のある遺伝子によってコードされるタンパク質の表面暴露の確率が、4つの異なる細胞局在化予測アルゴリズムの組み合わせによって決定された:Yloc(Briesemeister等,2010年)、TMHMM(http://www.cbs.dtu.dk/services/TMHMM/)、シグナルP(http://www.cbs.dtu.dk/services/シグナルP/)及びPhobius(Kail等,2007年)。特に、Ylocは、動物版で複数の予測モデルを提供する解釈可能なシステムである;本発明者等は、4箇所(細胞核、細胞質、ミトコンドリア、分泌経路)に予測するYLoc-LowRes及び9箇所(細胞外空間、血漿膜、細胞核、細胞質、ミトコンドリア、小胞体、ペルオキシソーム、ゴルジ装置及びリソソーム)に予測するYloc-HighResの両方を用いた。
全RNAがmiRCURY RNA単離キット(Exiqon)を用いて腫瘍Treg細胞(NSCLC又はCRC)から抽出され、そして1gがiScript逆転写スーパーミックス(BIORAD)を用いて逆転写された。その後、25ngのcDNAが、種々のアイソフォームを識別できる複数の遺伝子特異的プライマーを用いて、DreamTaq Green PCR Master Mix(ThermoScientific)で増幅された。PCR生成物が、アガロースゲル上で泳動された。特定の転写物の発現は、予想されたバンドサイズに基づいて評価された。
腫瘍浸潤CD4+T細胞の遺伝子発現状況を評価する為に、本発明者等は、2つの異なる腫瘍(NSCLC及びCRC)から、隣接する正常組織から、及び末梢血サンプルから種々のCD4+リンパ球サブセットを単離した。全てのこれらの組織から、本発明者等は、フローサイトメトリー(図1A及び図6A及び図6B)によってCD4+Treg細胞(18の個体からの36個のサンプル)、Th1細胞(21の個体からの30個のサンプル)及びTh17細胞(14の個体からの22個のサンプル)を精製した(表I及び表II)。
RNA配列決定によってプロファイルされた各細胞サブセットについて、診断時の年齢、性別、喫煙習慣(肺癌患者について)、臨床病理学的段階(TNM分類)腫瘍ヒストタイプ(histotype)及び等級(grade)を含む患者記録が示されている。
次に、本発明者等は、腫瘍浸潤Treg細胞が特異的な遺伝子発現パターンによって定義されることができるかどうかを尋ねた。
次に、本発明者等は、腫瘍浸潤Treg細胞の署名遺伝子の示差的発現プロファイルについて単一細胞レベルを調べた。本発明者等は、5個のCRCサンプル及び5個のNSCLC腫瘍サンプルから並びに健康な人の5個のPBMCsからCD4+T細胞を単離し(表II)、Treg細胞を精製し、そして自動化されたマイクロ流体システム(C1 Fluidigm)を用いて、単一細胞(合計858個のTreg細胞:CRCから320個及びNSCLCから286個;健康なヒトのPBMCsから252個)を捕捉した。次に、本発明者等は、高度に発現された(>10 FKPM)腫瘍Treg細胞署名遺伝子のうちの79個の遺伝子の発現をハイスループットRT-qPCR(Biomark HD,Fluidigm)によって評価した(図3A、図3C及び図7)。
次に、本発明者等は、CRC及びNSCLCの湿潤性Treg細胞、隣接の正常組織、並びに患者PBM中に存在する10個の代表的な署名遺伝子のタンパク質発現をフローサイトメトリーによって単一細胞レベルで評価された。10個のタンパク質のうち、2個はTreg細胞生物学との関連性が実証されているタンパク質(OX40及びTIGIT)(Joller等.,2014年;Voo等.,2013年)、7個はその発現が腫瘍浸潤Treg細胞において記載されたことがないタンパク質(BATF、CCR8、CD30、IL-1R2、IL-21R、PDL-1及びPDL-2)、1つのタンパク質、4-1 BB、は幾つかの造血細胞上で発現される補助刺激分子受容体であり、そのTreg細胞上での発現は、抗原活性化細胞をマーク付けすることが示されている(Schoenbrunn等.,2012年)。我々の知見は、全てのこれらのタンパク質が、正常組織に存在するTreg細胞と比較して、腫瘍浸潤Treg細胞において異なる程度で上方制御された(図4A及び図4B)ことを示した。
我々の知見を臨床成果と相関させる試みにおいて、本発明者等は、腫瘍-Treg署名転写物の発現がCRC患者及びNSCLC患者における疾病予後と相関するかどうかを尋ねた。それ故に、本発明者等は、177人のCRC患者のコーホート(GSE17536(Smith等.,2010年)の及び263人のNSCLC患者のコーホート(GSE41271-(Sato等.,2013年)の切除された腫瘍組織から得られたTreg署名遺伝子トランスクリプトーム・データセットの発現を調査し、そして、5年生存データと高い及び低い遺伝子発現レベルと相関された。発現が腫瘍浸潤Treg細胞において高度に豊富化されているそれらの遺伝子の中で、LAYN、MAGEH1及びCCR8は、それらがより選択的に発現される3つの遺伝子である場合に選択された(図9A〜図9C)。切断された腫瘍組織内のT細胞密度における差を正規化する為に、本発明者等は、選択された署名遺伝子とCD3Gとの発現の間の比率のを使用した。注目すべきことに、3つの署名遺伝子の高発現が、全ての場合において有意に減少した生存率と相関することが見出された(図5A)。興味深いことに、3つの署名遺伝子の発現がCRC患者の腫瘍病期分類とともに増加することがまた観察された(図5B)。
328個の遺伝子によってコードされ、公共データベースEnsEMBL(http://www.ensembl.org)で検索可能な全ての注釈付きタンパク質アイソフォームが、4つの予測アルゴリズムを用いて同時に分析され、そして表面暴露されるべきであると予測される少なくとも1つのアイソフォームをコードする遺伝子が潜在的標的として考慮された。328個の遺伝子のうち、193個が、4つの予測子のうちの少なくとも1つに基づいて少なくとも1つの潜在的細胞表面タンパク質アイソフォームをコードする。膜に関連付けられていると予測されるタンパク質アイソフォームのリストが、表VIにおいて報告されている。
腫瘍-Tregの潜在的標的において検証されるべき重要な局面は、細胞局在化アルゴリズムによって暴露された表面/関連付けられた膜であると予測されるタンパク質アイソフォームが実際に腫瘍Treg細胞において発現されることである。従って、全RNAがNSCLCサンプル又はCRCサンプルから単離された腫瘍Treg細胞から抽出され、そして各遺伝子について注釈付けされた種々のアイソフォームを識別することができる特異的プライマー対を用いてRT-PCRに付された。腫瘍Treg細胞において暴露され且つ検出された表面であると予測されるタンパク質アイソフォームの例示的な結果が表VIIにおいて報告される。その上、SIRPGについて実行されたRT-PCR分析の例が、図10において報告されている。
腫瘍浸潤Treg細胞の多様性は、それらの機能的関連性及び種々のタイプの癌における予後的意義を理解する為に、及び腫瘍浸潤Treg細胞の選択的枯渇を通じてTreg細胞調節の治療有効性をおそらく改善する為に十分に解明されるべきである。CRC及びNSCLCの湿潤性T細胞上で行われるトランスクリプトーム解析は、腫瘍浸潤Treg細胞が循環Treg及び正常組織湿潤Tregの両方とは異なることを示し、腫瘍微環境がTreg細胞における特異的遺伝子発現に影響を及ぼすことを示唆する。我々の知見はさらに、種々の組織からのTreg細胞が環境因子によって種々の遺伝子発現プロファイルを示すように指示されるという見解を支持する(Panduro等.,2016年)。事実、署名遺伝子のリストは、種々の腫瘍型から単離された腫瘍浸潤Treg細胞において一貫して上方制御される多数の分子を含み、及びこれらの署名遺伝子は、本発明者等が腫瘍浸潤Treg細胞を特異的にプロファイリングしなければ識別されていなかっただろう。腫瘍湿潤Treg署名遺伝子は、CRC湿潤性細胞とNSCLC湿潤性細胞との間で大部分共有されているだけでなく、乳癌及び胃癌において並びにCRC転移性腫瘍及びNSCLC転移性腫瘍(肝臓及び脳それぞれ)において保存されていることがわかり、これらの遺伝子の発現は、腫瘍微環境内のTreg細胞特異的機能と相関しうる腫瘍浸潤Treg細胞の共通特徴であることを示唆する。リンパ球に対する免疫チェックポイントの機能に関する我々の知識はまだ不完全であるが、チェックポイントを標的とするアゴニスト又はアンタゴニストのモノクロナール抗体は臨床開発中である。興味深いことに、これらのチェックポイント(例えば、GITR、OX40、TIGIT、LAG-3及びTIM-3)の幾つか及びそれらのリガンド(例えば、OX40LG、ガレクチン-9、CD70)の幾つかはまた腫瘍浸潤Treg細胞においても上方制御されていることが見つけられ、そしてこの事実はチェックポイント阻害剤での臨床結果の解釈において考慮されるべきである。実際には、腫瘍浸潤リンパ球の様々なサブセットにおけるチェックポイントの発現及びそれらのリガンドの評価は、相反する結果を明らかにし、且つ併用療法の理論的根拠を提供するのに役立つであろうと思われる。それ故に、チェックポイントの発現パターンは、腫瘍浸潤リンパ球及び腫瘍細胞の両方において評価されるべきである。選択された腫瘍Treg署名遺伝子での分析は、全トランスクリプトームデータを確認し、且つこれらの遺伝子の発現頻度に関する情報を提供した。腫瘍浸潤Treg細胞は、増大したサプレッサ活性、例えば十分に特徴付けられたOX40、CTLA4及びGITR、に関連付けられている高頻度遺伝子を発現する。その上、その特異的発現がタンパク質レベルでまた検証された、興味深く期待されていない多くの遺伝子がある。例えば、IL-1R2上方制御は、腫瘍内在性Treg細胞がエフェクター細胞上のIL-1β機能の中和を通じて抗腫瘍免疫応答を弱めるために別のメカニズムであることができる。PD-L1及びPD-L2発現は、活性化されたT細胞又はAPCで最近報告されている(Boussiotis等.,2014年;Lesterhuis等.,2011年;Messal等.,2011年)が、我々の知る限りでは、PD-L2もPD-L1のいずれの発現もTreg細胞において報告されておらず、及びそれらが腫瘍浸潤Treg細胞において過剰発現されているという我々の知見は、腫瘍微環境内のPD1/PD-Ls免疫調節性軸に追加のレベルの複雑さを加える。BATFは、Th17展開及びCD8+T細胞分化に主に関連している転写因子である(Murphy等.,2013年)。我々の知見は、BATF転写物が腫瘍浸潤Th17細胞よりも腫瘍浸潤Treg細胞において上方制御されることを示す(図8)。興味深いことに、CD8+T細胞におけるBATFの発現はIL-21によって誘発され(Xin等.,2015年)、そしてIL21Rが腫瘍浸潤Treg細胞において高度に発現されることが見出された(図4)。
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Claims (26)
- 腫瘍浸潤制御性T細胞において選択的に脱制御される少なくとも1つのマーカーの発現及び/又は機能を調節することができる分子であって、腫瘍の阻止及び/又は処置における使用の為の上記分子。
- 上記少なくとも1つのマーカーに特異的に結合し且つ抗体依存性の細胞介在性細胞傷害活性(ADCC)を誘発することができる、請求項1に記載の使用の為の分子。
- 上記腫瘍浸潤制御性T細胞を選択的に枯渇させることができる、請求項1又は2に記載の使用の為の分子。
- 下記からなる群から選択される、請求項1〜3のいずれか1項に記載の使用の為の分子:
a) 抗体又はそのフラグメント;
b) ポリペプチド;
c) 小分子;
d) 上記の抗体又はポリペプチドをコードするポリヌクレオチド又はそれらの機能的誘導体;
e) ポリヌクレオチド、例えばアンチセンス構築物、アンチセンスオリゴヌクレオチド、RNA干渉構築物又はsiRNA、
e) d)又はe)において定義されるポリヌクレオチドを含む又は発現するベクター;
f) 上記のポリペプチド若しくは抗体を発現する又はd)若しくはe)において定義されるポリヌクレオチドを含む、遺伝子的に組み換えられた宿主細胞。 - 上記マーカーが下記からなる群から選択され、ここで、下記のマーカー名のそれぞれが、「Ensembl gene id」によって特徴付けられており且つその中に開示されたアイソフォームタンパク質配列の全てを含む、請求項1〜4のいずれか1項に記載の分子。
- 上記マーカーが、膜貫通タンパク質、サイトカイン、エピジェネティック因子、キナーゼホスファターゼ又は転写因子からなる群から選択される、請求項5に記載の使用の為の分子。
- 上記マーカーが、SEQ ID NO:1-661からなる群から選択される膜貫通タンパク質である、請求項6に記載の使用の為の分子。
- 上記マーカーが、下記からなる群から選択される、請求項7に記載の使用の為の分子:LAYN(SEQ ID NO:1-9)、CCR8(SEQ ID NO:10-11)、IL21R(SEQ ID NO:12-14)、IL1R2(SEQ ID NO:206-209)、LY75(SEQ ID NO:78)、SIRPG(SEQ ID NO:122-126)、CD177(SEQ ID NO:651-653)、CD7(SEQ ID NO:549-554)、FCRL3(SEQ ID NO:452-457)、CADM1(SEQ ID NO:570-583)、NTNG2(SEQ ID NO:621-622)、CSF2RB(SEQ ID NO:134-137)、SECTM1(SEQ ID NO:349-356)、TSPAN5(SEQ ID NO:497-503)、TMPRSS3(SEQ ID NO:448-451)、TMPRSS6(SEQ ID NO:605-611)、METTL7A(SEQ ID NO:600-604)、THADA(SEQ ID NO:237)、NDFIP2(SEQ ID NO:148-151)、CHRNA6(SEQ ID NO:392-394)。
- 上記マーカーが、LAYN(SEQ ID NO:1-9)、CCR8(SEQ ID NO:10-11)、IL21R(SEQ ID NO:12-14)からなる群から選択される、請求項8に記載の使用の為の分子。
- 上記サイトカインが、IL32(SEQ ID NO:19-30)、IL7(SEQ ID NO:168-174)、EBI3(SEQ ID NO:175)、SECTM1(SEQ ID NO:349-356)、CSF1(SEQ ID NO:585-592)及びLTA(SEQ ID NO:657-658)からなる群から選択される、請求項6に記載の使用の為の分子。
- 上記エピジェネティック因子が、TDRD3(SEQ ID NO:712-718)、KAT2B(SEQ ID NO:719)、FOXA1(SEQ ID NO:720-721)及びRCBTB1(SEQ ID NO:722-723)からなる群から選択される、請求項6に記載の使用の為の分子。
- 上記キナーゼホスファターゼが、GSK3B(SEQ ID NO:724-725)、SSH1(SEQ ID NO:111-112)、CDK6(SEQ ID NO:726-727)、MINPP1(SEQ ID NO:181-183)、PTPRJ(SEQ ID NO:395-400)、CALM3(SEQ ID NO:728-735)及びPTP4A3(SEQ ID NO:593-598)からなる群から選択される、請求項6に記載の使用の為の分子。
- 上記転写因子が、VDR(SEQ ID NO:204)、ZNF334(SEQ ID NO:736-741)、CREB3L2(SEQ ID NO:565-567)、ETV7(SEQ ID NO:31又は32)、SOX4(SEQ ID NO:735)、TWIST1(SEQ ID NO:743-745)、TP73(SEQ ID NO:746-756)、FOXP3、NFE2L3(SEQ ID NO:76)、ARNTL2(SEQ ID NO:757-764)、BATF(SEQ ID NO:765-766)、PTTG1(SEQ ID NO:767-770)、HIVEP3(SEQ ID NO:771-772)、FOXA1(SEQ ID NO:720-721)、ZBTB38(SEQ ID NO:561)、FOXM1(SEQ ID NO:773-778)、TADA3(SEQ ID NO:779-782)、NFAT5(SEQ ID NO:160,783-791,742)からなる群から選択される、請求項6に記載の使用の為の分子。
- 上記マーカーが、MAGEH1(SEQ ID NO:708又は709)である、請求項1〜5のいずれか1項に記載の使用の為の分子。
- 上記腫瘍が、固形又は液性の腫瘍である、請求項1〜14のいずれか1項に記載の使用の為の分子。
- 上記固形の腫瘍が非小細胞肺癌、結腸直腸癌、乳癌、胃癌からなる群から選択される、又は該腫瘍が転移癌、好ましくは骨、脳若しくは肝臓の転移癌、である、請求項15に記載の使用の為の分子。
- 上記転移癌が、結腸直腸癌又は非小細胞肺癌に由来する、請求項16に記載の使用の為の分子。
- 対象者における腫瘍浸潤制御性T細胞をイン・ビボで枯渇させる為の方法において使用する為の又は対象者における腫瘍免疫を高める為の方法において使用する為の請求項1〜14のいずれか1項に記載の分子。
- 請求項1〜14のいずれか1項に記載の分子と少なくとも1つの医薬的に許容される担体とを含む医薬組成物。
- 治療剤、好ましくは抗腫瘍剤における治療剤、をさらに含む、請求項19に記載の医薬組成物。
- 腫瘍の阻止及び/又は処置において使用する為の、又は、
対象者における腫瘍浸潤制御性T細胞をイン・ビボで枯渇させる為の方法において使用する為の、又は、
対象者における腫瘍免疫を高める為の方法において使用する為の、
請求項19又は20に記載の医薬組成物。 - 対象者における腫瘍の発生の危険を予測する及び/又は診断する及び/又は評価する為の、及び/又は対象者における腫瘍の進行を監視する為の、及び/又は対象者における腫瘍の治療的処置の有効性を監視する為の、及び/又は対象者における腫瘍の治療的処置をスクリーニングする為のイン・ビトロ方法であって、
a) 上記対象者から得られた単離された生物学的サンプルにおいて、請求項1〜14のいずれか1項に記載のマーカーの少なくとも1つを検出すること、そして
b) 適切な対照と比較すること
の工程を含む、上記方法。 - 対象者における腫瘍の発生の危険を予測する及び/又は診断する及び/又は評価する為の、及び/又は対象者における腫瘍の進行を監視する為の、及び/又は対象者における腫瘍の治療的処置の有効性を監視する為の、及び/又は対象者における腫瘍の治療的処置をスクリーニングする為の、請求項22に記載のイン・ビトロ方法であって、検出されるべきマーカーがLAYN、MAGEH1及びCCR8からなる群から選択される少なくとも1つのマーカーである、上記方法。
- 対象者における結腸直腸癌又は非小細胞肺癌を予測する為の請求項23に記載のイン・ビトロ方法であって、
a) 上記対象者から得られた単離された生物学的サンプルにおいて、LAYN、MAGEH1及びCCR8からなる群から選択される少なくとも1つのマーカーを検出すること、そして
b) 適切な対照と比較すること
の工程を含み、
対象者から得られた単離された生物学的サンプル中の上記少なくとも1つのマーカーの、対照量よりも高い量が、上記対象者が予後不良を有することを示す、上記方法。 - 腫瘍の処置及び/又は阻止の為の方法であって、請求項1〜14のいずれか1項に記載の分子を対象者に投与することを含む、上記方法。
- 抗腫瘍としての分子作用を識別する為の方法であって、
請求項1〜14のいずれか1項に記載の少なくとも1つのマーカーに対する候補分子の結合特異性について該候補分子をアッセイすること;
請求項1〜14のいずれか1項に記載の少なくとも1つのマーカーに対する特異的結合活性を有する分子を選択すること;
好ましくは腫瘍浸潤制御性T細胞を選択的に枯渇させることによって、より好ましくは抗体依存性の細胞介在性細胞傷害活性(ADCC)を誘発することによって、増殖を阻害する及び/又は細胞系においてアポトーシス応答を誘発する能力について該特異的結合分子を試験すること
の工程を含む、上記方法。
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