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

Abstract

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 þ 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 breast cancer cells orthotopically in wild-type or Cxcr3 À/À 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 þ 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 þ T-cell infiltration, with enhanced effector function. CD8 þ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8 þ T cells and the antitumor effects of ExTr were abrogated in Cxcr3 À/À 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 þ 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.

The Effects of Physical Activity on Cancer Patients Undergoing Treatment with Immune Checkpoint Inhibitors: A Scoping Review

“…The studies ranged in time of publication from 2018 to 2021. Three of the studies were pre-clinical randomized control trials [ 18 , 19 , 20 ] and one was a prospective clinical cohort pilot study [ 21 ]. The most common form of physical activity was running a treadmill [ 19 , 20 ], and PD-1/PD-L1 inhibitors were used in all studies.…”

“…Three of the studies were pre-clinical randomized control trials [ 18 , 19 , 20 ] and one was a prospective clinical cohort pilot study [ 21 ]. The most common form of physical activity was running a treadmill [ 19 , 20 ], and PD-1/PD-L1 inhibitors were used in all studies. Two of the studies examined the response in melanoma tumors [ 18 , 21 ], one considered breast tumor response [ 19 ], and one utilized non-small cell lung cancer (NSCLC) [ 20 ].…”

“…The main focuses of the pre-clinical studies were tumor size and growth rate [ 18 , 19 , 20 ]. All three murine studies indicated that physical activity slowed tumor growth, slowed immune cell proliferation, and improved immune sensitivity [ 18 , 19 , 20 ].…”

“…Gomes-Santos et al studied the effect of physical activity, concurrent with anti-PD-1 alone or in combination with anti-CTLA-4 treatment, on tumor growth and the tumor environment [ 19 ]. The study used mice to model human breast cancer and treadmills for physical activity.…”

Estrogen-Receptor-Positive Breast Cancer in Postmenopausal Women: The Role of Body Composition and Physical Exercise

“…The mechanisms involved in these processes are complex and multifaceted and may be mediated, at least in part, by a reduction in inflammation markers, particularly MCP-1 and IL-6 [105], and the reduced expression of the transcription factor NF-κB [107]. To date, most of the main findings regarding the molecular mechanisms involving physical exercise and tumorigenesis were obtained in preclinical models available elsewhere [108][109][110][111][112].…”