Exercise-Induced Engagement of the IL-15/IL15Ra axis Promotes Anti Tumor Immunity

The advent of immune checkpoint blockade has improved patient outcomes, providing durable disease control by reversing localized tumor-mediated immune-suppression and promoting anti-tumor immunity. Despite successes in melanoma and lung cancer, these therapies have largely failed in pancreatic ductal adenocarcinoma (PDA); a 'cold' tumor with the highest mortality rate among all major cancers. PDA is uniquely characterized by multiple intra-pancreatic tumor- and stroma-induced mechanisms of immune-suppression, and there remains a great need to explore creative approaches to improve anti-tumor immune responses in this disease. Herein, we show routine aerobic exercise provides tumor-protective benefits in murine PDA through modulation of both systemic and intra-tumoral immunity. Reversing immune-suppressive properties of both myeloid and T cell populations, we found the anti-tumor benefits of exercise require CD8 T cell activation and expansion in the tumor. Specifically, we report the sub-population of IL15Ra+ CD8 T cells is required for exercise-induced tumor protection and anti-tumor immunity, both of which are abrogated in the context IL-15 blockade. We further show that exercise-induced increases in intra-tumoral T cells are governed by adrenergic signaling and S1P-gradient dependent lymphocyte migration. Finally, we found that combination with aerobic exercise sensitizes pancreatic tumors to anti-PD-1 therapy. Overall, our work highlights the unique mechanisms governing exercise-induced tumor protection in PDA, and uncovers the importance of the interplay between systemic and intra-tumoral immunity to develop innovative strategies to reverse immune-suppression in this devastating disease. Overall design: In this work, we set out to peform unibased analysis of the tumor immune microenvironment in pancretic cancer tumors in response to aerobic exercise. All live leukocytes in control and exercised tumors were isolated and were assessed for changes in the relative proportion of specific immune populations or changes to the transcriptional phenotype within each immune cell subset. Differences in the immune cell infiltrates of control and exercised mice would be used to inform mechanistic insights for exercise-induced tumor protection in pancreatic cancer.

免疫检查点阻断（immune checkpoint blockade）疗法的问世改善了患者的临床结局，通过逆转肿瘤局部介导的免疫抑制、激活抗肿瘤免疫，实现了持久的疾病控制。尽管在黑色素瘤与肺癌中取得了显著成效，但此类疗法在胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDA）中却鲜有突破；胰腺导管腺癌是所有实体瘤中死亡率最高的“冷肿瘤”。该疾病的独特之处在于存在多种胰腺内肿瘤与基质诱导的免疫抑制机制，目前仍亟需探索创新性策略，以改善其抗肿瘤免疫应答。

本研究证实，常规有氧运动可通过调控系统性免疫与瘤内免疫，在小鼠胰腺导管腺癌模型中发挥肿瘤保护作用。在逆转髓系细胞与T细胞群体的免疫抑制特性后，我们发现运动的抗肿瘤益处依赖于肿瘤内CD8⁺ T细胞的激活与扩增。具体而言，我们发现IL15受体α阳性（IL15Ra+）的CD8⁺ T细胞亚群是运动诱导肿瘤保护与抗肿瘤免疫所必需的，且这两种效应在IL-15阻断的条件下均会被完全消除。我们进一步证实，运动诱导的瘤内T细胞浸润增加，受肾上腺素能信号通路与鞘氨醇-1-磷酸（S1P）梯度依赖性淋巴细胞迁移调控。最后，我们发现联合有氧运动可使胰腺肿瘤对抗PD-1治疗增敏。

综上，本研究阐明了运动诱导胰腺导管腺癌肿瘤保护的独特机制，并揭示了系统性免疫与瘤内免疫之间的相互作用在逆转该毁灭性疾病免疫抑制中的重要价值，为开发创新性治疗策略提供了依据。

实验总体设计：本研究旨在探究有氧运动应答状态下胰腺癌肿瘤的肿瘤免疫微环境，并进行无偏分析。我们分离了对照组与运动组小鼠肿瘤中的活性白细胞，随后评估了特定免疫群体的相对比例变化，以及各免疫细胞亚群内的转录表型改变。对照组与运动组小鼠的免疫细胞浸润差异，将用于阐释运动诱导胰腺癌肿瘤保护的分子机制。