Journal for immunotherapy of cancer
MGPhi cancer-associated fibroblasts orchestrate MDSC-mediated immunosuppression in melanoma through TNF signaling
By Tu L, Yi M, Feng Z and 8 others.
Abstract
Background
Melanoma is an aggressive skin cancer with a highly immunosuppressive tumor microenvironment. This study investigated the role of matrix Gla protein (MGP)-high cancer-associated fibroblasts (MGPhi CAFs) in melanoma progression and their potential relevance to immunotherapy.
Methods
Single-cell RNA sequencing and tissue validation were used to characterize MGP expression, and its association with prognosis was analyzed. In vitro assays and mouse melanoma models were used to investigate the effects of MGPhi CAFs on tumor progression, myeloid-derived suppressor cell (MDSC) recruitment and apoptosis. The role of MDSCs was further examined by adoptive transfer. The antitumor effects of vitamin K2, anti-programmed cell death protein 1 (PD-1) and their combination were evaluated in vivo. Normality was assessed using the Shapiro-Wilk test. Group differences were analyzed using two-tailed paired or unpaired Student’s t-tests or one-way or two-way analysis of variance followed by Tukey’s multiple comparisons test. Survival curves were compared using the log-rank test.