Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade.
Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade.
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DOI：
10.1016/j.medj.2022.07.008
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发表时间：
2022-10-14
期刊：
影响因子：
17
通讯作者：
Restifo, Nicholas P.
中科院分区：
文献类型：
--
作者：
Palmer, Douglas C.;Webber, Beau R.;Patel, Yogin;Johnson, Matthew J.;Kariya, Christine M.;Lahr, Walker S.;Parkhurst, Maria R.;Gartner, Jared J.;Prickett, Todd D.;Lowery, Frank J.;Kishton, Rigel J.;Gurusamy, Devikala;Franco, Zulmarie;Vodnala, Suman K.;Diers, Miechaleen D.;Wolf, Natalie K.;Slipek, Nicholas J.;McKenna, David H.;Sumstad, Darin;Viney, Lydia;Henley, Tom;Burckstummer, Tilmann;Baker, Oliver;Hu, Ying;Yan, Chunhua;Meerzaman, Daoud;Padhan, Kartik;Lo, Winnie;Malekzadeh, Parisa;Jia, Li;Deniger, Drew C.;Patel, Shashank J.;Robbins, Paul F.;McIvor, R. Scott;Choudhry, Modassir;Rosenberg, Steven A.;Moriarity, Branden S.;Restifo, Nicholas P.
肿瘤浸润淋巴细胞（TIL）的连续转移不能持续引起肿瘤排斥反应。因此，操纵抑制T细胞效应子功能和新抗原识别的内在因子可以改善TIL治疗结果。我们以前确定了细胞因子诱导的SH 2蛋白（CISH）作为小鼠T细胞功能亲合力的关键调节因子。在这里，我们研究了CISH在实体瘤中调节人T细胞效应子功能的机制作用，并证明了CISH的CRISPR/Cas9破坏增强了TIL新抗原识别和对检查点阻断的应答。单细胞基因表达谱用于鉴定患者来源的TIL中高CISH表达和TIL活化之间的负相关性。开发了符合GMP的CRISPR/Cas9基因编辑过程以评估CISH破坏对人外周血T细胞和TIL的分子和功能表型的影响。将具有破坏的Cish功能的肿瘤特异性T细胞过继转移到荷瘤小鼠中，并在有或没有检查点阻断的情况下评估功效。CISH表达与T细胞功能障碍有关。使用CRISPR/Cas9删除CISH导致超活化并提高对肿瘤源性新抗原的功能亲和力，而不会干扰T细胞成熟。Cish敲除导致体内对检查点阻断的易感性增加。CISH负调节人T细胞效应子功能，并且其遗传破坏提供了改善过继性TIL疗法的治疗功效的新途径。T细胞的基因工程有可能提高其破坏肿瘤细胞的功效。Palmer等人证明，CISH的敲除导致改善的T细胞活化和功能，并且当与PD 1阻断剂组合时，在临床前体内模型中促进肿瘤消退和存活。
Adoptive transfer of tumor infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation of intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the Cytokine-induced SH2 protein (CISH) as a key regulator of T cell functional avidity in mice. Here, we investigate the mechanistic role of CISH in regulating human T cell effector function in solid tumors and demonstrate that CRISPR/Cas9 disruption of CISH enhances TIL neoantigen recognition and response to checkpoint blockade. Single-cell gene expression profiling was used to identify a negative correlation between high CISH expression and TIL activation in patient-derived TIL. A GMP-compliant CRISPR/Cas9 gene editing process was developed to assess the impact of CISH disruption on the molecular and functional phenotype of human peripheral blood T cells and TIL. Tumor-specific T cells with disrupted Cish function were adoptively transferred into tumor-bearing mice and evaluated for efficacy with or without checkpoint blockade. CISH expression was associated with T cell dysfunction. CISH deletion using CRISPR/Cas9 resulted in hyperactivation and improved functional avidity against tumor derived neoantigens without perturbing T cell maturation. Cish knockout resulted in increased susceptibility to checkpoint blockade in vivo. CISH negatively regulates human T cell effector function, and its genetic disruption offers a novel avenue to improve the therapeutic efficacy of adoptive TIL therapy. Genetic engineering of T cells has the potential to improve their efficacy in destroying tumor cells. Palmer et al. demonstrate that knockout of CISH results in improved T cell activation and function, and when combined with PD1 blockade, promotes tumor regression and survival in a preclinical in vivo model.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
4.4
作者：
Houtman, JCD;Houghtling, RA;Samelson, LE
通讯作者：
Samelson, LE
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
46.9
作者：
Hendel A;Bak RO;Clark JT;Kennedy AB;Ryan DE;Roy S;Steinfeld I;Lunstad BD;Kaiser RJ;Wilkens AB;Bacchetta R;Tsalenko A;Dellinger D;Bruhn L;Porteus MH
通讯作者：
Porteus MH