Elucidating Mechanism of Immune Evasion in Head and Neck Cancers

项目摘要/摘要 为了更好地了解头颈部癌症的免疫逃逸机制， 增强他们对免疫治疗的敏感性。大约90%的头颈癌是鳞状细胞癌 癌症(HNSCC)。复发或转移性HNSCC正在接受检查点封锁治疗 针对程序性死亡1(PD-1)的免疫治疗，PD-1是T细胞上的共同抑制受体。然而，只有一个 部分HNSCC患者对这种抗PD-1治疗有反应(10%-20%)。因此，迫切需要 阐明单一阻断PD-1治疗无反应的潜在机制。除PD-1外，T 细胞表达其他共抑制受体，这些受体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，这些受体在免疫中的作用仍不明确。 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 肿瘤浸润性淋巴细胞(TIL)的异质性模式；然而，其背后的分子驱动因素 差异免疫表型在很大程度上仍不清楚。我们建议的研究完成后，可能会产生 对决定检查点封锁成败的机制的新见解 免疫疗法。我们期望我们的研究能够勾勒出人类神经干细胞的全面免疫格局。 人类病人。所获得的知识将为改进免疫治疗提供关键步骤 以更合理的设计靶向更多的共抑制受体并克服功能障碍 TIL的进展。 我们的长期目标是阐明免疫逃逸机制并改进治疗策略。 HNSCC。HNSCC的发生通常与癌基因突变有关，例如 Smad4、PIK3CA功能增益突变或Notch1功能丧失突变。它在很大程度上仍然 未知HNSCCs是如何逃避免疫识别的。为了解决这个问题，我们用一种 KrasG12D突变和Smad4缺失联合造成的移植性鳞癌模型(KRS-SCC)。我们 发现KRS-SCC肿瘤完全逃脱T细胞介导的抗肿瘤反应，表现为 耗竭的CD8和CD4TIL共表达PD-1和LAG-3。一致地，PD-1和LAG-3的双重抑制 抑制KRS-SCCs的生长。我们计划使用我们独特的小鼠模型和人类患者 以进一步阐明HNSCCs的免疫逃避机制。我们提议的研究可能 大大提高了我们对单一PD-1阻断治疗失败的机制的理解。 与公共卫生的相关性。我们预计，我们的研究将在理解 PD-1阻断治疗HNSCCs失败的机制。我们期待着我们的提议 研究将揭示肿瘤细胞的内在特性与TIL免疫信号之间的联系。 这些研究不仅解决了癌症免疫学中的基本问题，而且还为 在目标人群中开发HNSCCs新疗法的基础 设计合理化。

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.