Mechanisms of immunotherapy response and resistance in pancreatic ductal adenocarcinoma

胰腺导管腺癌免疫治疗反应和耐药机制

基本信息

批准号：
10210061
负责人：
Ingunn Margarete Stromnes
金额：
$ 43.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210061
关键词：
Address Affinity Agonist Amino Acids Animal Model Animals Antigens Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cancer Etiology Cell physiology Cells Chimera organism Chronic Clinical Clinical Trials Clone Cells Combination immunotherapy Combined Modality Therapy Cytokine Receptors Cytokine Signaling Data Detection Diagnosis Disease Engineering Event Failure Fibroblasts Functional disorder Genes Goals Granzyme Human Immune Immunologic Surveillance Immunotherapy Impairment In Vitro Inflammatory Interferon Type II Interleukin-10 Knowledge Lead Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mus Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Outcome PD-1 inhibitors PD-L1 blockade PDL1 pathway Pancreatic Ductal Adenocarcinoma Patients Peripheral Pilot Projects Positioning Attribute Production Proteins Research Resistance Role Series Signal Transduction T cell differentiation T-Cell Receptor T-Lymphocyte T-cell receptor repertoire TNF gene TNFRSF5 gene Testing Therapeutic Time Tumor Antigens Tumor Escape anti-PD-L1 antigen-specific T cells antitumor effect base cancer therapy cell killing cell type cellular targeting cytokine design effective therapy effector T cell engineered T cells exhaust exhaustion immune checkpoint blockade in vivo mesothelin mortality neoplastic cell novel overexpression pancreatic cancer model pancreatic cancer patients pre-clinical programmed cell death protein 1 programs public health relevance rare cancer response safety testing standard of care therapy resistant tool transcription factor translational approach tumor tumor eradication tumor immunology tumor microenvironment

项目摘要

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.

项目概要胰腺导管腺癌 (PDA) 是一种致命疾病，众所周知，对包括免疫在内的治疗具有抵抗力与此同时，针对 PD-1:PD-L1 通路的免疫疗法正在引发令人震惊的结果。尽管进行了数十年的癌症免疫学研究，但其他晚期恶性肿瘤的临床结果。控制胰腺癌免疫监视的潜在机制在很大程度上是未知的。部分原因是缺乏允许在不同阶段检测肿瘤特异性 T 淋巴细胞的动物模型。我们通过创造新的动物来填补这一知识空白。根据我们最近的研究，允许随着时间的推移询问罕见的肿瘤抗原特异性 T 细胞的模型。发现，我们现在准备好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药物我们令人信服的初步数据支持基于免疫的联合疗法。假设免疫介导的胰腺癌根除需要 1) 高亲和力的组合肿瘤特异性 T 细胞，2) 修饰抑制性肿瘤内骨髓细胞，3) 克服慢性我们筛选了一系列免疫疗法并确定了 TNFα 介导的炎症信号传导。激动性 αCD40 或 PD-L1 阻断仅具有短暂的抗肿瘤活性，而组合会导致 63% 动物的肿瘤根除未能重振肿瘤内 T 细胞功能。相反，改变了外周肿瘤特异性 T 细胞库并扩展了独特的外周 T 细胞富含促生存基因和 Ikzf2 的亚群相比之下，激动性 αCD40 具有有效的促进作用。短命的溶细胞瘤内 T 细胞，与瘤内骨髓细胞 IL-27 的减少相关最后，消除非肿瘤/宿主细胞的 Tnfr1 表达可以克服导致肿瘤逃逸的问题。 αCD40+αPD-L1 治疗动物的肿瘤 100% 根除在目标 1 中，我们将鉴定功能性肿瘤。 PD-L1 后 TCR 库改变和 Ikzf2+ T 细胞亚群诱导的意义在目标 2 中，我们将测试激动性 αCD40 是否通过废除来促进有效的溶细胞效应 T 细胞。在目标 3 中，我们将鉴定瘤内骨髓细胞产生的 IL-27 和/或 CD8 T 细胞产生的 IL-10。非肿瘤/宿主细胞上的 IFNγ 和 TNFα 信号传导如何在组合后导致不同的结果胰腺癌的免疫疗法并测试一种包含 TNFα 的新型组合免疫疗法与 CD40 激动剂和 PD-1 抑制剂联合阻断这些研究旨在确定一种药物。胰腺癌 T 细胞功能障碍的机制基础，并制定可行的临床策略克服这一难题，目标是为胰腺癌患者创造一种安全有效的基于免疫的治疗方法。