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

Tetsuro Taki,Yoshinori Hasegawa,Takayuki Fukui,Masahide Takahashi,Yuki Miyai,Naoya Asai,Tetsunari Hase,Shinji Mii,Hiroyoshi Nishikawa,Yuichi Ando,Kazuki Nishida,Daisuke Sugiyama,Hiroki Kobayashi,Yukihiro Shiraki,Toyofumi Fengshi Chen-Yoshikawa,Atsushi Enomoto

doi:10.26508/lsa.202101230

Tetsuro Taki, Yoshinori Hasegawa + Show 14 more

Open Access

https://doi.org/10.26508/lsa.202101230

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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.

Highlights

As immune checkpoint blockade (ICB) therapy is emerging as a promising treatment strategy for a wide range of cancers, understanding the mechanisms underlying tumor immunity and identifying biomarkers that predict patient outcomes has been a focus of cancer research (Rizvi et al, 2015; Kumagai et al, 2020a, 2020b; House et al, 2020; Mager et al, 2020; Smith et al, 2021)
Meflin is a marker of Cancer-associated fibroblasts (CAFs) present in the stroma of invasive non-small cell lung cancer (NSCLC) tumors We first examined the expression of Meflin in human lung adenocarcinoma (LUAD) tissues
These data showed that Meflin is a marker of CAFs that accumulate in the invasive stages of both human and mouse LUAD

Summary

Introduction

As immune checkpoint blockade (ICB) therapy is emerging as a promising treatment strategy for a wide range of cancers, understanding the mechanisms underlying tumor immunity and identifying biomarkers that predict patient outcomes has been a focus of cancer research (Rizvi et al, 2015; Kumagai et al, 2020a, 2020b; House et al, 2020; Mager et al, 2020; Smith et al, 2021). Single-cell analysis of tumor stroma provided evidence of similar CAF populations in other cancer types, such as breast and lung cancer (Costa et al, 2018; Lambrechts et al, 2018; Kieffer et al, 2020). A pioneering study showed that the CAF-S1 subset, which is characterized by α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) expression, is crucial for the induction of regulatory T cells to promote cancer progression and immunotherapy resistance (Costa et al, 2018; Kieffer et al, 2020). Another study revealed that the infiltration of CAFs expressing leucine-rich repeat-containing 15 (LRRC15), whose expression was induced by TGF-β, correlated with poor response to ICB therapy across multiple cancer types (Dominguez et al, 2020). A complete picture of the roles of diverse CAFs in tumor immunity and responses to ICB is still lacking It is unclear whether a specific CAF subset enhances the efficacy of ICB therapy

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