Abstract A216: Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade

Debattama R. Sen, Brian C. Miller, Rose Al Abosy, K. Bi, M. LaFleur, K. Yates, Ana Lako, K. Felt, G. S. Naik, M. Manos, E. Gjini, Yamini V. Virkud, Stephen F. Hodi, S. Rodig, A. Sharpe, W. Haining
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引用次数: 0

Abstract

T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is effective only in a minority of patients. The basis for T-cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T-cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models as well as patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T-cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “stem-like exhausted” T-cells that have a distinct regulatory state. Stem-like exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, stem-like exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Stem-like exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy without reversion of their exhausted epigenetic state. CD8+ T-cells with a stem-like exhausted phenotype can be found in human melanoma samples and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Responsiveness to checkpoint blockade is therefore restricted to a subpopulation of exhausted TILs that retain specific functional properties which enable them to control tumors. Approaches to expand stem-like exhausted CD8+ T-cells in the tumor microenvironment may be an important component of improving checkpoint blockade response. Citation Format: Debattama R. Sen, Brian C. Miller, Rose Al Abosy, Kevin Bi, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen D. Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Yamini V. Virkud, Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T-cells mediate tumor control and response to checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A216.
衰竭CD8+ t细胞的功能特异性亚群介导肿瘤控制和对检查点阻断的反应
肿瘤微环境中的t细胞功能障碍(TME)是许多癌症的标志。通过PD-1检查点阻断t细胞功能的恢复可以导致显著的临床反应,但仅在少数患者中有效。TME中t细胞功能障碍的基础,以及抗pd -1治疗作用于功能障碍t细胞的机制尚不完全清楚。在这里,我们表明抗pd -1治疗作用于黑色素瘤小鼠模型和黑色素瘤患者的CD8+肿瘤浸润淋巴细胞(TILs)的特定亚群。我们发现功能失调的CD8+ til具有典型的t细胞耗竭的表观遗传和转录特征,反映了慢性病毒感染中所见的特征。与慢性病毒感染类似,耗尽的CD8+ til包含一个具有独特调节状态的“干样耗尽”t细胞亚群。茎样耗尽til也具有大多数“最终耗尽”til所不具有的关键功能属性:它们保留更多的多功能性,在转移到荷瘤小鼠后持续存在,并分化以在TME中重新填充最终耗尽的til。因此,干细胞样耗尽的CD8+ til比最终耗尽的细胞更能控制肿瘤的生长。干细胞样耗尽,但不是最终耗尽,CD8+ TILs可以响应抗pd -1治疗,而不会逆转其耗尽的表观遗传状态。具有干样耗竭表型的CD8+ t细胞可以在人类黑色素瘤样本中发现,并且在肿瘤中具有较高比例的该亚群的患者对联合检查点阻断治疗的反应持续时间显着延长。因此,对检查点封锁的反应仅限于保留特定功能特性的耗尽til亚群,这些特性使它们能够控制肿瘤。在肿瘤微环境中扩增干细胞样耗尽CD8+ t细胞的方法可能是改善检查点阻断反应的重要组成部分。引文格式:Debattama R. Sen, Brian C. Miller, Rose Al Abosy, Kevin Bi, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen D. Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Yamini V. Virkud, Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining。功能特化的耗尽CD8+ t细胞亚群介导肿瘤控制和对检查点阻断的反应[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr A216。
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