Elucidating Mechanism of Immune Evasion in Head and Neck Cancers

项目概要/摘要 更好地了解头颈癌的免疫逃避机制至关重要， 增强他们对免疫疗法的敏感性。大约90%的头颈癌是鳞状细胞癌 癌（HNSCC）。复发性或转移性HNSCC正在接受检查点阻断治疗 免疫疗法靶向程序性死亡1（PD-1），T细胞上的共抑制受体。但只有 HNSCC患者亚组对这种抗PD-1疗法有反应（10-20%）。因此，迫切需要 阐明对PD-1单次阻断无反应性的治疗机制。除了PD-1，T 细胞表达其他共抑制受体，其也可以诱导免疫抑制表型，例如 淋巴细胞活化基因3（LAG-3）。然而，这种受体的作用在免疫系统中仍然不清楚。 逃避HNSCC（例如，LAG-3）。我们的初步数据显示，HNSCC患者表现出高度的 肿瘤浸润淋巴细胞（TIL）的异质性模式;然而，这种异质性模式的分子驱动因素可能与肿瘤浸润淋巴细胞（TIL）的异质性模式有关。 差异免疫表型仍然在很大程度上未知。完成我们建议的研究可能会产生 对决定检查点封锁成功或失败的机制的新见解 免疫疗法我们希望我们的研究能够描绘出HNSCC在免疫系统中的全面免疫景观。 人类病人所获得的知识将为改善免疫疗法提供关键步骤， 用更合理的设计靶向额外的共抑制受体， TILs的进展。 我们的长期目标是阐明免疫逃避机制，改善治疗策略， HNSCCs。HNSCC的发展通常与致癌突变有关，例如HNSCC基因的杂合缺失。 Smad 4、PIK 3CA的功能获得性突变或Notch 1的功能丧失性突变。在很大程度上， 尚不清楚HNSCC如何逃避免疫识别。为了解决这个问题，我们进行了研究， KrasG 12 D突变和Smad 4缺失联合引起的移植SCC模型（称为KRS-SCC）。我们 发现KRS-SCC肿瘤完全逃避了T细胞介导的抗肿瘤反应，表现为 共表达PD-1和LAG-3的耗尽的CD 8和CD 4 TIL。同时，PD-1和LAG-3的双重抑制 抑制KRS-SCC的生长。我们建议使用我们独特的小鼠模型和人类患者 以进一步阐明HNSCC的免疫逃避机制。我们建议的研究可能 实质上推进了我们对单一PD-1阻断治疗失败机制的理解。 与公共卫生的相关性。我们设想我们的研究将在理解 HNSCC中PD-1阻断治疗失败的机制。我们预计， 研究将揭示肿瘤细胞的内在特征和TIL的免疫特征之间的联系。 这些研究不仅解决了癌症免疫学的基本问题， 为在目标患者人群中开发HNSCCs的新疗法奠定了基础， 合理化设计。

Project Summary/Abstract It is crucial to better understand immune evasion mechanisms in head and neck cancers in order to enhance their susceptibility to immunotherapy. About 90% of head and neck cancers are squamous cell carcinomas (HNSCC). Recurrent or metastatic HNSCCs are being treated with checkpoint blockade immunotherapy targeting programmed death 1 (PD-1), a co-inhibitory receptor on T cells. However, only a subset of HNSCC patients responded to such anti-PD-1 therapy (10-20%). Thus, there is an urgent need to elucidate mechanisms underlying therapy unresponsiveness to single blockade of PD-1. Apart from PD-1, T cells express other co-inhibitory receptors that can also induce immunosuppressive phenotypes, such as lymphocyte activation gene-3 (LAG-3). However, the role of such receptors remains poorly defined in immune evasion of HNSCCs (e.g., LAG-3). Our preliminary data show that HNSCC patients exhibit a highly heterogeneous pattern of tumor infiltrating lymphocytes (TILs); however, the molecular drivers underlying such differential immune phenotypes remain largely unknown. Completion of our proposed studies may generate novel insight into the mechanisms that determine the success or failure of checkpoint blockade immunotherapy. We expect our studies to delineate the comprehensive immune landscape of HNSCCs in human patients. The knowledge gained would provide critical steps toward improving immunotherapy by targeting additional co-inhibitory receptors with a more rational design and overcoming the dysfunctional progression of TILs. Our long-term goal is to elucidate immune evasion mechanism and improve therapeutic strategies of HNSCCs. HNSCC development often associates with oncogenic mutations, such as heterozygous loss of Smad4, gain-of-function mutations of PIK3CA or loss-of-function mutations of Notch1. It remains largely unknown how HNSCCs evade immune recognition. To address this question, we performed studies with a transplanted SCC model caused by combining KrasG12D mutation and Smad4 loss (termed KRS-SCC). We found that KRS-SCC tumors completely escaped T cell-mediated anti-tumor responses, manifested with exhausted CD8 and CD4 TILs co-expressing PD-1 and LAG-3. Consistently, dual inhibition of PD-1 and LAG-3 suppressed the growth of KRS-SCCs. We propose to employ our unique mouse models and human patient samples to further elucidate immune evasion mechanisms of HNSCCs. Our proposed studies may substantially advance our understanding in mechanisms that underlie therapy failure of single PD-1 blockade. Relevance to public health. We envision that our studies will provide substantial advances in understanding the mechanisms that underlie therapy failure of PD-1 blockade in HNSCCs. We anticipate that our proposed studies will reveal the connection between intrinsic characteristics of tumor cells and immune signature of TILs. These studies not only address fundamental questions in cancer immunology but also lay a scientific foundation for developing novel therapy of HNSCCs in the targeted patient populations with a more rationalized design.