Meflin-positive cancer-associated fibroblasts enhance tumor response to immune checkpoint blockade

Abstract

Cancer-associated fibroblasts (CAFs) are an integral component of the tumor microenvironment (TME). Most CAFs shape the TME toward an immunosuppressive milieu and attenuate the efficacy of immune checkpoint blockade (ICB) therapy. However, the detailed mechanism of how heterogeneous CAFs regulate tumor response to ICB therapy has not been defined. Here, we show that a recently defined CAF subset characterized by the expression of Meflin, a glycosylphosphatidylinositol-anchored protein marker of mesenchymal stromal/stem cells, is associated with survival and favorable therapeutic response to ICB monotherapy in patients with non-small cell lung cancer (NSCLC). The prevalence of Meflin-positive CAFs was positively correlated with CD4-positive T-cell infiltration and vascularization within non-small cell lung cancer tumors. Meflin deficiency and CAF-specific Meflin overexpression resulted in defective and enhanced ICB therapy responses in syngeneic tumors in mice, respectively. These findings suggest the presence of a CAF subset that promotes ICB therapy efficacy, which adds to our understanding of CAF functions and heterogeneity.

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

“…As extensively reviewed in other review articles on CAFs, the state of CAFs, or whether a stroma is good or bad, may be associated with the tumor response to immune checkpoint inhibitors (ICIs), and there is accumulating evidence that CAF phenotypes are involved in anti-tumor immunity, which will not be reiterated here [ 1 , 2 , 3 , 4 , 5 , 51 , 52 ]. We recently showed that the number of Meflin + rCAFs is associated with a favorable objective response rate in patients with non-small-cell lung cancer treated with ICIs [ 53 ]. Again, this observation seems to contradict the prevailing notion that CAFs generally contribute to tumor resistance to ICIs [ 54 , 55 ].…”

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…The interactions between tumor cells and TME promote proliferation, differentiation, invasion, metastasis and even drug resistance [ 16 ]. Multiple components of TME contribute to the formation of an immunosuppressive microenvironment that promotes tumor immune escape, thus accelerating progression of these events, which can be attributed to hypoxia, metabolic dysfunction, immune cell phenotypic shift, and tumor-derived exosomes (Tu-Exo) [ 17 – 20 ]. As the most prevalent epigenetic modification of mRNA and non-coding RNA [ 21 ], m 6 A methylation achieves post-transcriptional control of protein expression through effects on RNA metabolism, in turn, influencing a wide range of cellular activities [ 10 ].…”

Characterization of aging cancer-associated fibroblasts draws implications in prognosis and immunotherapy response in low-grade gliomas

“…Previous studies have revealed that CAFs have context-dependent functions, harboring both tumor-promoting and tumor-suppressive roles ( Chen et al, 2021 ). The significant impact of CAFs on the regulation of anti-tumor immunity makes it possible to predict the immunotherapy response based on CAF-related biomarkers ( Miyai et al, 2022 ). Moreover, considering that cancer has been previously regarded as a disease of aging, CAFs are demonstrated to be particularly susceptible to aging-related impact in the context of tumor development ( Yasuda et al, 2021a ).…”

“…Tumor-suppressive roles of meflin-positive CAFs have been proposed, which are mediated by the regulation of collagen structures and bone morphogenetic protein (BMP) signaling in the TME ( Takahashi et al, 2021 ). Meflin has been also reported to correlate with favorable prognosis and therapeutic response to immune checkpoint blockage treatment in patients with non-small cell lung cancer (NSCLC) ( Miyai et al, 2022 ). Alternatively, meflin is determined as an unfavorable gene with a predictive value in patients with colon adenocarcinoma ( Wang et al, 2021 ).…”

“…However, only a minority of patients get a favorable response to immunotherapy ( Pitt et al, 2016 ). The T cell’s capacity to kill tumor cells is significantly affected by the tumor stromal microenvironment, in which CAFs are understood to be a key player in immunosuppressive activity and reduce the efficacy of immune checkpoint blockage treatment ( Baker et al, 2021 ; Miyai et al, 2022 ). Over the past decade, cancer has been usually recognized as a disease of aging and CAFs appear to be easily influenced by this age-related effect ( Fane and Weeraratna, 2020 ).…”