Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma

项目总结 胰腺导管腺癌(Pda)是一种致命的疾病，对包括免疫治疗在内的治疗方法产生了众所周知的抗药性。 检查站封锁。与此同时，针对PD-1：PD-L1途径的免疫治疗正在产生惊人的效果 其他晚期恶性肿瘤的临床转归。尽管进行了数十年的癌症免疫学研究， 控制胰腺癌免疫监视的潜在机制在很大程度上是未知的。这是应该的， 在一定程度上，这是由于缺乏动物模型，允许在不同的时期检测肿瘤特异性T淋巴细胞 临床结果通常在患者身上观察到。我们通过创造新的动物填补了这一知识空白 随着时间的推移，允许询问或罕见的肿瘤抗原特异性T细胞的模型。根据我们最近的调查 发现，我们现在唯一准备确定如何安全地促进抗原特异性T细胞介导的 破坏胰腺癌，我们的建议将利用这些结果来开发一种新的临床前 以免疫为基础的联合治疗为临床试验提供信息。我们令人信服的初步数据支持 免疫介导的胰腺癌根除需要结合高亲和力的假说 肿瘤特异性T细胞，2)修饰抑制性肿瘤内髓系细胞，3)克服慢性 肿瘤坏死因子α介导的炎症信号。我们筛选了一系列免疫疗法，并确定 激动型αCD40或PD-L1阻断仅具有短暂的抗肿瘤活性，而联合应用可导致 63%的动物肿瘤被根除。PD-L1阻断未能重振肿瘤内T细胞功能 取而代之的是改变了外周肿瘤特异性T细胞谱系，并扩增了一个独特的外周T细胞 富含支持生存基因和Ikzf2的亚群。相比之下，激动型αCD40促进有效，但 瘤内溶细胞T细胞与瘤内髓系细胞IL-27下降的相关性 制作。最后，通过非肿瘤/宿主细胞取消Tnfr1的表达克服了肿瘤逃逸导致的 在αCD40+αPD-L1治疗的动物中，肿瘤被100%清除。在目标1中，我们将确定功能 PD-L1后TCR谱和Ikzf2+T细胞亚群变化的意义 封锁。在目标2中，我们将测试激动型αCD40是否通过取消 瘤内髓系细胞产生IL-27和/或CD8 T细胞产生IL-10。在目标3中，我们将确定 干扰素γ和肿瘤坏死因子α在非肿瘤/宿主细胞上的信号如何导致联合治疗后不同的结果 胰腺癌的免疫治疗及包括肿瘤坏死因子α在内的新型联合免疫治疗 联合使用CD40激动剂和PD-1抑制剂进行阻断。这些研究旨在确定一种 探讨胰腺癌患者T细胞功能障碍的发病机制及临床治疗策略 克服它的目标是为胰腺癌患者创造一种安全有效的免疫治疗方法。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy including immune checkpoint blockade. Meanwhile, immunotherapy targeting the PD-1:PD-L1 pathway is inducing stunning clinical outcomes in other advanced malignancies. Despite decades of cancer immunology research, the underlying mechanisms governing immune surveillance in pancreas cancer are largely unknown. This is due, in part, to a lack of animal models that permit the detection of tumor-specific T lymphocytes during disparate clinical outcomes commonly observed in patients. We have filled this knowledge gap by creating novel animal models that permit the interrogation or the rare tumor-antigen specific T cells over time. Based on our recent discoveries, we are now uniquely poised to identify how to safely promote antigen-specific T cell-mediated destruction of pancreas cancer, and our proposal will use these results to develop a novel preclinical combination immune-based therapy to inform a clinical trial. Our compelling preliminary data support the hypothesis that immune-mediated pancreas cancer eradication requires a combination of a 1) high affinity tumor specific T cell, 2) modifying suppressive intratumoral myeloid cells, and 3) overcoming chronic inflammatory signaling mediated by TNFα. We screened a series of immunotherapies and identified that agonistic αCD40 or PD-L1 blockade has only transient antitumor activity whereas the combination leads to tumor eradication in 63% of animals. PD-L1 blockade failed to reinvigorate intratumoral T cell functions and instead changed the peripheral tumor-specific T cell repertoire and expands a unique peripheral T cell subpopulation enriched for pro-survival genes and Ikzf2. In contrast, agonistic αCD40 promotes potent, yet short-lived, cytolytic intratumoral T cells which correlates with a decrease in intratumoral myeloid cell IL-27 production. Finally, abrogating Tnfr1 expression by non-tumor/host cells overcomes tumor escape resulting in 100% of tumor eradication in αCD40+αPD-L1-treated animals. In Aim 1, we will identify the functional significance of the altered TCR repertoire and the Ikzf2+ T cell subpopulation induced following PD-L1 blockade. In Aim 2, we will test if agonistic αCD40 promotes potent cytolytic effector T cells by abrogating intratumoral myeloid cell production of IL-27 and/or CD8 T cell production of IL-10. In Aim 3, we will identify how IFNγ and TNFα signaling on non-tumor/host cells lead to disparate outcomes following combination immunotherapy of pancreas cancer and test a novel combinatorial immunotherapy that includes TNFα blockade in combination with a CD40 agonist and a PD-1 inhibitor. The studies are designed to identify a mechanistic basis for T cell dysfunction in pancreas cancer and to create a feasible clinical strategy to overcome it with the goal to create a safe and effective immune-based treatment for pancreas cancer patients.