TY - JOUR TI - Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade AU - Gomes-Santos, Igor L. AU - Amoozgar, Zohreh AU - Kumar, Ashwin S. AU - Ho, William W. AU - Roh, Kangsan AU - Talele, Nilesh P. AU - Curtis, Hannah AU - Kawaguchi, Kosuke AU - Jain, Rakesh K. AU - Fukumura, Dai T2 - Cancer Immunology Research AB - The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer (BC), we examined here the causal role of CD8+ T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C BC cells orthotopically in wild-type or Cxcr3-/- female mice and initiated intensity-controlled ExTr sessions when tumors reached ~100 mm3. We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8+ T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti-PD-1 alone or in combination with anti-CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion, and decreased hypoxia. ExTr boosted CD8+ T-cell infiltration, with enhanced effector function. CD8+ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3-/- mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway. ExTr also sensitized ICB-refractory BCs to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8+ T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of BC. DA - 2021/01/01/ PY - 2021 DO - 10.1158/2326-6066.CIR-20-0499 DP - cancerimmunolres.aacrjournals.org J2 - Cancer Immunol Res LA - en SN - 2326-6066, 2326-6074 UR - https://cancerimmunolres.aacrjournals.org/content/early/2021/03/31/2326-6066.CIR-20-0499 Y2 - 2021/04/13/18:30:00 ER -