Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer,Cancer Cell

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Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer
Cancer Cell ( IF 48.8 ) Pub Date : 2022-06-02 , DOI: 10.1016/j.ccell.2022.05.006
Emma Kurz ₁ , Carolina Alcantara Hirsch ₂ , Tanner Dalton ₃ , Sorin Alberto Shadaloey ₁ , Alireza Khodadadi-Jamayran ₄ , George Miller ₅ , Sumedha Pareek ₆ , Hajar Rajaei ₇ , Chirayu Mohindroo ₇ , Seyda Baydogan ₇ , An Ngo-Huang ₈ , Nathan Parker ₉ , Matthew H G Katz ₁₀ , Maria Petzel ₁₁ , Emily Vucic ₁₂ , Florencia McAllister ₁₃ , Keri Schadler ₆ , Rafael Winograd ₁₄ , Dafna Bar-Sagi ₁₂

Affiliation

Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
Department of Cell Biology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
Department of Pathology, Columbia University Irving Medical Center, 630 W 168th St., New York, NY 10032, USA.
Applied Bioinformatics Laboratory, NYU Grossman School of Medicine, 227 East 30(th) St., New York, NY 10016, USA.
Department of Surgery, Trinity Health New England, 56 Franklin St., Waterbury, CT 06706, USA.
Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Department of Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Department of Health Outcomes and Behavior, Moffit Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Department of Clinical Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Gastrointestinal Medical Oncology and Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston TX, 77030, USA.
Permultter Cancer Center, NYU Langone Health, 160 East 34(th) St., New York, NY 10016, USA.

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.

中文翻译：

运动诱导的 IL-15/IL-15Rα 轴参与可促进胰腺癌的抗肿瘤免疫

有氧运动与降低癌症发病率和癌症相关死亡率有关。然而，人们对运动对胰腺导管腺癌（PDA）的影响知之甚少，目前这种疾病的治疗选择有限。在此，我们证明有氧运动通过调节全身和肿瘤内免疫来减少 PDA 肿瘤的生长。从机制上讲，运动促进免疫动员和肿瘤浸润 IL15Rα CD8 T 细胞的积累，从而发挥肿瘤保护作用。在临床样本中，还观察到肿瘤内 CD8 T 细胞的运动依赖性增加。 IL-15 超级激动剂 (NIZ985) 治疗强调了白细胞介素 (IL)-15/IL-15Rα 轴的转化潜力，可减弱肿瘤生长、延长生存期并增强对化疗的敏感性。最后，运动或 NIZ985 都能使胰腺肿瘤对 αPD-1 敏感，从而改善抗肿瘤和生存益处。总的来说，我们的研究结果强调了运动-肿瘤学轴的治疗潜力，并将 IL-15 激活确定为治疗这种致命疾病的一种有前途的治疗策略。

更新日期：2022-06-02

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