TY - JOUR
T1 - Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer
AU - Kurz, Emma
AU - Hirsch, Carolina Alcantara
AU - Dalton, Tanner
AU - Shadaloey, Sorin Alberto
AU - Khodadadi-Jamayran, Alireza
AU - Miller, George
AU - Pareek, Sumedha
AU - Rajaei, Hajar
AU - Mohindroo, Chirayu
AU - Baydogan, Seyda
AU - Ngo-Huang, An
AU - Parker, Nathan
AU - Katz, Matthew H.G.
AU - Petzel, Maria
AU - Vucic, Emily
AU - McAllister, Florencia
AU - Schadler, Keri
AU - Winograd, Rafael
AU - Bar-Sagi, Dafna
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/7/11
Y1 - 2022/7/11
N2 - 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.
AB - 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.
KW - checkpoint blockade
KW - exercise
KW - IL-15
KW - immunology
KW - immunotherapy
KW - pancreatic cancer
KW - PD-1
KW - super-agonist
KW - T cell
UR - http://www.scopus.com/inward/record.url?scp=85133659176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133659176&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.05.006
DO - 10.1016/j.ccell.2022.05.006
M3 - Article
C2 - 35660135
AN - SCOPUS:85133659176
SN - 1535-6108
VL - 40
SP - 720-737.e5
JO - Cancer cell
JF - Cancer cell
IS - 7
ER -