TY - JOUR
T1 - Aerobic Exercise Alters the Melanoma Microenvironment and Modulates ERK5 S496 Phosphorylation
AU - Savage, Hannah
AU - Pareek, Sumedha
AU - Lee, Jonghae
AU - Ballarò, Riccardo
AU - Minussi, Darlan Conterno
AU - Hayek, Karma
AU - Sadullozoda, Mumina
AU - Lochmann, Brooke S.
AU - McQuade, Jennifer L.
AU - LaVoy, Emily C.
AU - Marmonti, Enrica
AU - Patel, Hetal
AU - Wang, Guangyu
AU - Imanishi, Masaki
AU - Kotla, Sivareddy
AU - Abe, Jun Ichi
AU - Schadler, Keri
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a phenotypic shift in the tumor-associated macrophage population and increased the expression of MHC class II transcripts. We further demonstrated that ERK5 S496A knock-in mice, which are phosphorylation deficient at the S496 residue, "mimicked" the exercise effect when unexercised, yet when exercised, these mice displayed a reversal in the effect of exercise on tumor growth and macrophage polarization compared with wild-type mice. Taken together, our results reveal tumor-specific differences in the immune response to exercise and show that ERK5 signaling via the S496 residue plays a crucial role in exercise-induced tumor microenvironment changes. See related Spotlight by Betof Warner, p. 1158.
AB - Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a phenotypic shift in the tumor-associated macrophage population and increased the expression of MHC class II transcripts. We further demonstrated that ERK5 S496A knock-in mice, which are phosphorylation deficient at the S496 residue, "mimicked" the exercise effect when unexercised, yet when exercised, these mice displayed a reversal in the effect of exercise on tumor growth and macrophage polarization compared with wild-type mice. Taken together, our results reveal tumor-specific differences in the immune response to exercise and show that ERK5 signaling via the S496 residue plays a crucial role in exercise-induced tumor microenvironment changes. See related Spotlight by Betof Warner, p. 1158.
KW - Animals
KW - Mice
KW - CD8-Positive T-Lymphocytes
KW - Melanoma/genetics
KW - Phenotype
KW - Phosphorylation
KW - Tumor Microenvironment
KW - Mitogen-Activated Protein Kinase 7
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U2 - 10.1158/2326-6066.CIR-22-0465
DO - 10.1158/2326-6066.CIR-22-0465
M3 - Article
C2 - 37307577
AN - SCOPUS:85171657598
SN - 2326-6066
VL - 11
SP - 1168
EP - 1183
JO - Cancer immunology research
JF - Cancer immunology research
IS - 9
ER -