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 - Funding Information:
This work was supported in part by funding from the Cancer Prevention Research Institute of Texas (CPRIT RP190256), which supported H. Savage, R. Ballarò, M. Imanishi, J.-i. Abe, and K. Schadler. K. Schadler and J. Lee were
Funding Information:
This work was supported in part by funding from the Cancer Prevention Research Institute of Texas (CPRIT RP190256), which supported H. Savage, R. Ballaro, M. Imanishi, J.-i. Abe, and K. Schadler. K. Schadler and J. Lee were supported in part by funding from a Career Enhancement Program award of The University of Texas MD Anderson Cancer Center SPORE in Melanoma provided by the NCI (5P50CA221703-04). H. Savage was supported by CPRIT RP170067 during the completion of this work. H. Savage and D. Conterno Minussi were supported by a fellowship from the Schissler Foundation. S. Pareek was funded by the Pauline Altman-Goldstein Foundation Discovery Fellowship. J.-i. Abe was supported in part by grants from the NIH (AI-156921 and CA016672). The Advanced Cytometry & Sorting Core Facility and Flow Cytometry and Cellular Imaging Facility at MD Anderson, utilized for flow cytometry experiments, are supported by NCI P30CA016672. We would like to acknowledge the MD Anderson CPRIT Single Core (CPRIT RP180684) for processing and sequencing the scRNA-seq samples in this paper. Thank you to Nicholas Navin and all the members of the core including Tuan Tran, Anna Casasent, Jerome Lin, and Jianzhou Li for their input in experimental design and data interpretation. We would like to thank Aislyn Schalck for help guiding and interpreting single-cell immune cell data. Supplementary Figure S4A was created with BioRender.com.
Funding Information:
J.-i. Abe reports grants from NIH and CPRIT during the conduct of the study; grants from NIH outside the submitted work. K. Schadler reports grants from Cancer Prevention Research Institute of Texas, NCI, Schissler Foundation, and Pauline
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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UR - http://www.scopus.com/inward/citedby.url?scp=85171657598&partnerID=8YFLogxK
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 -