Overcoming the immune evasion mechanism of Merkel cell polyomavirus-associated Merkel cell carcinoma

项目摘要 肿瘤免疫逃逸是癌症免疫治疗的主要障碍，然而， 其潜在机制仍然知之甚少。这项探索性研究的目标是 建议克服默克尔细胞癌(MCC)的免疫逃避机制， 与默克尔细胞多瘤病毒(MCPyV)相关的高致命性皮肤癌。目前，有 转移性MCC尚无有效的治疗方法。很大一部分MCC对 免疫检查点疗法。免疫抑制是MCPyV的重要危险因素- 关联的MCC。此外，在免疫功能正常的90%以上的MCC患者中， 尽管产生了识别MCPyV编码的T细胞，MCC肿瘤仍在继续发展 癌蛋白在肿瘤中表达。肿瘤浸润性MCPyV特异性T细胞对 改善了患者的存活率，但它们在极小比例的MCC中很少出现 并显示出显著的激活减少。这些观察结果支持与MCPyV相关的 MCCS可能通过限制T细胞在肿瘤内的侵袭而逃脱免疫破坏 抑制T细胞活化。然而，潜在的机制在很大程度上是未知的。我们 最近发现干扰素基因的刺激物(STING)在 MCPyV+MCCs。因为刺痛功能对于感知癌细胞中受损的DNA是至关重要的 刺激细胞因子的产生、瘤内CD8+T细胞的浸润和抗肿瘤的T细胞 反应，我们假设MCC中的刺痛沉默与其免疫抑制有关 巨噬细胞集落刺激因子的性质及其再激活可促进T细胞的浸润和抗肿瘤作用 细胞毒性。为了验证这一假设，我们开发了一种新的方法来专门激活 刺伤MCC，但不刺伤其他人类细胞。此方法将与工程化相结合 人T细胞、MCC小鼠异种移植模型以及人源化小鼠肿瘤模型 确定STING重新激活对刺激T细胞在肿瘤内的渗透的功能影响 和抗肿瘤免疫反应。因为STING信号对于增强 检查点抑制剂的抗肿瘤效果，我们将结合我们新的刺痛-再激活方法 与PD-1阻断实现协同抗肿瘤活性，规避MCC耐药 免疫检查点疗法。这些研究有可能克服MCC 免疫逃逸机制和开发新的治疗策略来治疗高度 侵袭性MCC癌症。我们的研究也可能揭示一种新的策略来克服 传统的人类刺痛激动剂治疗的毒性和局限性。

Project Summary Tumor immune escape represents a major obstacle in cancer immunotherapy, however, the underlying mechanism remains poorly understood. The goal of this exploratory research proposal is to overcome the immune evasion mechanism of Merkel cell carcinoma (MCC), a highly lethal skin cancer associated with merkel cell polyomavirus (MCPyV). Currently, there is no effective therapeutic treatment for metastatic MCCs. A large portion of MCCs is resistant to the immune checkpoint therapies. Immuno-suppression is an important risk factor for MCPyV- associated MCC. Furthermore, in more than 90% of MCC patients with normal immune function, MCC tumors continue to develop despite the production of T cells recognizing MCPyV-encoded oncoproteins expressed in the tumors. Tumor-infiltrating MCPyV-specific T cells are critical for improved patient survival, and yet they are sparsely present in a very small percentage of MCCs and show significantly reduced activation. These observations support that MCPyV-associated MCCs may escape immunological destruction by restricting T-cell intratumoral infiltration and repressing T cell activation. However, the underlying mechanisms are largely unknown. We recently discovered that Stimulator of Interferon Genes (STING) is completely silenced in MCPyV+ MCCs. Because STING function is critical for sensing damaged DNA in cancer cells to stimulate cytokine production, intratumoral CD8+ T cell infiltration, and antitumor T cell responses, we hypothesize that STING silencing in MCC contributes to its immune suppressive nature and that reactivation of STING in MCCs can stimulate T cell infiltration and antitumor cytotoxicity. To test this hypothesis, we have developed a novel approach to specifically activate STING in MCC but not other human cells. This approach will be combined with engineered human T cells, an MCC mouse xenograft model, as well as a humanized mouse tumor model to define the functional impact of STING reactivation on stimulating T cell intratumoral infiltration and antitumor immune responses. Because STING signaling is also important for enhancing the antitumor efficacy of checkpoint inhibitors, we will combine our new STING-reactivating method with PD-1 blockade to achieve synergistic antitumor activity and circumvent MCC resistance to immune checkpoint therapies. These studies have the potential to overcome the MCC immunoescape mechanism and develop novel therapeutic strategies to treat the highly aggressive MCC cancers. Our study may also reveal a novel strategy for overcoming the toxicity and limitation of traditional human STING agonist-based therapies.