TP53/17p杂合性缺失促进结直肠癌免疫逃逸的分子机制研究

肠癌是威胁我国人民健康的恶性肿瘤，免疫逃逸是肠癌患者死亡的主要原因。虽然PD1抗体已被成功应用于肠癌等多种癌症，但仍只有不到30%的患者产生良好应答。因此，研究肿瘤如何产生免疫治疗抵抗的分子机制是急需解决的科学问题。抑癌基因TP53与人类多种癌症的发生和发展密切相关。多年来，申请人一直围绕筛选TP53/17p缺失肿瘤的精准治疗靶点开展了深入研究，发现与TP53共缺失的看家基因POLR2A为过半肠癌治疗提供了新的打击靶点。然而，TP53/17p的生物学功能特别是在如何调节免疫逃逸的分子机制尚不清楚？我们初步研究提示17p缺失可特异性地促进MDSCs的浸润和抑制性微环境的形成，并受到PPARδ信号通路调控。基于科学假设，本项目将从动物和临床等多个层面，着重研究17p通过PPARδ/CCL2-CCR2信号轴调控MDSCs浸润的分子机制。本课题的完成将为肠癌的治疗提供新的理论依据和潜在的治疗靶点。

Colorectal cancer (CRC) is third most common type of cancer diagnosed in China and immune evasion is the leading course of of cancer-related death. Although PD1 checkpoint inhibition has been successfully applied to the treatment of multiple difficult-to-treat tumor types including CRC, there was only less than 30% of patient will have durable clinical responses. There is now an urgent need to identify mechanisms of resistance, to predict outcome and to identify targets for combination therapy. TP53, a well-known tumor suppressor gene, is frequently inactivated by mutation or deletion in many types of human tumors. A tremendous effort has been made to restore p53 activity for cancer therapies but with no success. Our recent studies found suppression of POLR2A selectively inhibits proliferation, survival and tumorigenic potential of CRC cells with hemizygous TP53/17p loss, which, for the first time, opened a novel therapeutic window for over half of human CRC tumors. However, the biological functions of TP53/17p during tumorigenesis, especially its role in immune evasion is still elusive. Our preliminary data found that the hemizygous loss of TP53/17p could activate PPARδ signaling pathway, which in turn promotes myeloid-derived suppressor cells (MDSCs) infiltration to the tumor microenvironment, indicating the fundamental role of TP53/17p loss during immune-suppressive microenvironment formation and immune evasion. Using animal models and clinical samples, we will pinpoint the detailed molecular mechanisms of how TP53/17p loss promotes MDSCs migration via PPARδ/CCL2-CCR2 axis. Our study will help to understand the molecular mechanisms of immune evasion and provide a novel therapeutic strategy for 17p-deficient CRC patients.