A Role for TLR2 in Regulating Immune Surveillance in Pancreatic Ductal Adenocarcinoma

摘要 免疫疗法对一些实体癌患者显示出显着的益处。然而，它在很大程度上 对于胰腺导管腺癌（PDAC）的治疗无效。值得注意的是，伴有肝转移的癌症 通常表现出对免疫治疗的反应性降低，并且PDAC通常转移到肝脏。我们 实验室先前已经表明，PDAC在早期疾病发病过程中触发肝脏炎症， 随后支持转移到肝脏。然而，目前还不清楚肝脏如何影响 免疫治疗的结果。肝脏通常被称为免疫调节器官，参与调节 T细胞耐受性初步数据显示，血清淀粉样蛋白A（SAA）蛋白释放的肝脏在设置 在PDAC小鼠模型中，PDAC发育的基因缺失抑制T细胞监视， 将PDAC肿瘤从T细胞“贫乏”转化为T细胞“丰富”。已知SAA通过Toll样受体2发出信号 与此一致，初步数据也表明TLR 2的遗传缺失导致T细胞浸润， 甚至在存在高水平SAA的情况下也能进入PDAC肿瘤。这一发现暗示了SAA/TLR 2信号转导 作为PDAC中T细胞监视的决定因素。然而，关于TLR 2如何调节T细胞， 癌症中的细胞监测。这一提议的核心假设是TLR 2信号传导导致 将肿瘤特异性效应T细胞隔离在肝脏中，然后进行细胞凋亡，从而 限制了PDAC中的生产性T细胞监视。为了验证这一假设，在目标一中，我将定义细胞 TLR 2调节PDAC中T细胞监视的机制。在目标二中，我将确定 TLR 2对肿瘤特异性T细胞命运和T细胞免疫疗法的功效。总的来说，本提案中的研究 将提高我们对肿瘤外在特征在PDAC中调节免疫抵抗的作用的理解 其目的是鉴定用于提高免疫疗法功效的新策略。该项目将 由一位在癌症免疫学和肿瘤生物学方面具有专长的知名导师赞助。此次赞助 需要在一个具有特殊癌症培训环境的机构中坚定地致力于指导 免疫学和肿瘤生物学。该项目还包括一个严格的研究生培训计划，以补充 教学法科学研究培训以及科学交流和教学培训。

ABSTRACT Immunotherapy has shown remarkable benefit for some patients with solid cancers. However, it has largely been ineffective for the treatment of pancreatic ductal adenocarcinoma (PDAC). Notably, cancers with liver metastasis often show decreased responsiveness to immunotherapy and PDAC commonly metastasizes to the liver. Our lab has previously shown that PDAC triggers liver inflammation during early disease pathogenesis that subsequently supports metastasis to the liver. However, it remains unclear how the liver might influence outcomes to immunotherapy. The liver is classically known as an immunoregulatory organ involved in regulating T cell tolerance. Preliminary data show that serum amyloid A (SAA) proteins released by the liver in the setting of PDAC development suppress T cell surveillance in mouse models of PDAC such that genetic deletion of SAA converts PDAC tumors from T cell “poor” to T cell “rich”. SAA are known to signal through toll-like receptor 2 (TLR2) and consistent with this, preliminary data also show that genetic deletion of TLR2 causes T cell infiltration into PDAC tumors even in the presence of high levels of SAA. This finding implicates the SAA/TLR2 signaling pathway as a determinant of T cell surveillance in PDAC. However, little is known about how TLR2 regulates T cells surveillance in cancer. It is the central hypothesis of this proposal that TLR2 signaling causes sequestration of tumor-specific effector T cells in the liver which then undergo apoptosis, thereby limiting productive T cell surveillance in PDAC. To test this hypothesis, in Aim One I will define cellular mechanisms by which TLR2 regulates T cell surveillance in PDAC. In Aim Two, I will determine the impact of TLR2 on tumor-specific T cell fate and the efficacy of T cell immunotherapy. Altogether, studies in this proposal will improve our understanding of the role of tumor-extrinsic features in regulating immune resistance in PDAC with the aim to identify novel strategies for improving the efficacy of immunotherapy. This project will be sponsored by an established mentor with expertise in cancer immunology and tumor biology. This sponsorship entails a strong commitment to mentorship at an institution with an exceptional environment for training in cancer immunology and tumor biology. The project also includes a rigorous graduate training plan to complement training in scientific research with didactics and training in scientific communication and teaching.