Exercise Training Improves Tumor Control by Increasing CD8(+) T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade

Author(s)

Gomes-Santos, Igor L. ^{[1, 2]} ; Amoozgar, Zohreh ^{[1, 2]} ; Kumar, Ashwin S. ^{[1, 3, 2]} ; Ho, William W. ^{[1, 2]} ; Roh, Kangsan ^{[1, 2]} ; Talele, Nilesh P. ^{[1, 2]} ; Curtis, Hannah ^{[1, 2]} ; Kawaguchi, Kosuke ^{[1, 2, 4]} ; Jain, Rakesh K. ^{[1, 2]} ; Fukumura, Dai ^{[1, 2]}

Affiliation

^[1] Harvard Med Sch, Boston, MA 02115 - USA

^[2] Massachusetts Gen Hosp, Edwin L Steele Labs, Dept Radiat Oncol, 100 Blossom St, Cox 736, Boston, MA 02114 - USA

^[3] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

^[4] Kyoto Univ, Dept Breast Surg, Grad Sch Med, Kyoto - Japan

• Document type: Journal article
• Source: CANCER IMMUNOLOGY RESEARCH; v. 9, n. 7, p. 765-778, JUL 2021.
• Web of Science Citations: 0

Abstract

Y The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer, 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. Weimplanted E0771, EMT6, MMTV-PyMT, and MCa-M3C breast cancer cells orthotopically in wild-type or Cxcr3(-/-) female mice and initiated intensity-controlled ExTr sessions when tumors reached approximately 100 mm(3). 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 by 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 breast cancers 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 breast cancer. (AU)

• FAPESP's process: 14/13690-8 - Role of exercise training on prevention of cardiotoxicity provoked by doxorubicin
• Grantee: Igor Lucas Gomes dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/21320-1 - Influence of aerobic exercise on drug delivery and doxorubicin-based chemotherapy response in obesity-associated breast cancer
• Grantee: Igor Lucas Gomes dos Santos
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor