Abstract LB165: Exercise training boosts CTL infiltration and sensitizes tumors to immune checkpoint blockade
Authors: Gomes-Santos Igor L. 
Published: July 2021

Abstract
Exercise training boosts CTL infiltration and sensitizes tumors to immune checkpoint blockade
Igor L. Gomes-Santos, Zohreh Amoozgar, Ashwin S. Kumar, William W. Ho, Rakesh K. Jain, Dai Fukumura Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital & Harvard Medical School, Boston, MA, USA.
Exercise can promote health and beneficial effects on cancer patients. However, how exercise training (ExTr) induces antitumor effects is not well understood. We investigated underlining mechanisms by which ExTr regulates the tumor microenvironment (TME) and therapeutic response to immunotherapy in murine breast cancer (BC) models – E0771 and MCa-M3C grown in syngeneic female mice (C57BL/6 and FVB, respectively). We started intensity-controlled ExTr (45 min daily sessions at 60% of maximal capacity, moderate-to-vigorous intensity on a running treadmill) when tumors reached 100 mm3. ExTr with this regimen certainly delayed tumor growth in both models. We then performed flow cytometry, RNA-seq, ELISA, and immunohistochemistry to characterize the effects of ExTr on TME. ExTr normalized abnormal tumor vasculature – indicated by the increased pericyte coverage and perfusion, reduced hypoxia in both models. Also, ExTr induced a shift in metabolic signature towards oxidative metabolism and enhanced antitumor immunity, accessed by RNA-seq. ExTr boosted CD8+ T cell infiltration, with enhanced effector function (higher IFNγ, Granzyme B, TNFα cytokine production) and proliferation (Ki67 expression). The therapeutic benefits of ExTr depend on CD8+ T cells, as its selective depletion with anti-CD8β antibody abrogates the exercise-mediated tumor control. Importantly, ExTr selectively boosted CD8+ T cell infiltration without affecting other T cells subsets or myeloid cells. Mechanistically, we found that ExTr enhances the CXCL9/11-CXCR3 chemokine system that mediates CD8+ T cell infiltration to tumors, as the recruitment of CD8+ T cells and antitumor effects of ExTr were abrogated in Cxcr3-/- mice (C57BL/6 background). We further tested treatments with immune checkpoint blockade (ICB) consisted of anti-PD-1 alone or in combination with anti-CTLA-4. Indeed, ExTr sensitized refractory BCs to the ICB therapies. Taken together, we established that ExTr induces vascular normalization in established BCs and improves perfusion, oxygenation, and oxidative metabolism. Importantly, ExTr boosts CD8+ T cell infiltration and function and induces CD8+ T cell-dependent antitumor effects and sensitization to ICB therapies. Since exercise has already been recommended to cancer patients as supportive care, implementing ExTr into a clinical investigation should be relatively straightforward. Our findings and mechanistic insights provide a strong rationale for the clinical translation of ExTr as a physiological intervention.
Citation Format: Igor L. Gomes-Santos. Exercise training boosts CTL infiltration and sensitizes tumors to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB165.