Cancer-Associated Fibroblasts Suppress CD8+ T-cell Infiltration and Confer Resistance to Immune-Checkpoint Blockade

Abstract

Immune checkpoint blockade (ICB) promotes anti-tumor immune responses and can result in durable patient benefit. However, response rates in breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the breast tumor microenvironment and have known immunosuppressive functions in addition to their well-established roles in directly promoting tumor growth and metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models to show that CAF abundance is associated with insensitivity to combination αCTLA-4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathological analyses demonstrating a relationship between CAF density and a CD8+ T cell-excluded tumor phenotype. The CAF receptor Endo180 (Mrc2) is predominantly expressed on myofibroblastic CAFs, and its genetic deletion depleted a subset of αSMA-expressing CAFs and impaired tumor progression in vivo. Addition of wild-type, but not Endo180-deficient, CAFs in co-implantation studies restricted CD8+ T cell intratumoral infiltration, and tumors in Endo180 knockout mice exhibited increased CD8+ T cell infiltration and enhanced sensitivity to ICB compared to tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors was associated with a poor response to αPD-1 therapy, highlighting the potential benefits of therapeutically targeting a specific CAF subpopulation in breast and other CAF-rich cancers to improve clinical responses to immunotherapy.

Update on triple‐negative breast cancers – highlighting subtyping update and treatment implication

“…The myofibroblastic CAFs accumulated differentially in TNBC and promoted accumulation of regulatory T cells in human breast cancers 109 . CAF abundance was found to be associated with the immune‐excluded phenotype and insensitivity to ICB in a mouse breast cancer model 110 . In addition, the alterations in TNBC could promote ICB resistance.…”

Targeting the tumor stroma for cancer therapy

“…The antigen crosspresentation driven by CAFs could negatively modulate T cells function and survival [296]. Mechanistically, PD-1 ligand 2 (PD-L2) expressed by CAFs induces T cell anergy and even death through the interaction with PD-1.…”

Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors

“…CAFs form a “shell” of sorts around the tumor, which is especially effective at preventing T-cell infiltration. A recent study confirms that CD8+ T-cell infiltration in breast cancer tumors is directly correlated with the strength of the CAF barrier, due not only to physical barrier but also due to secreted factors that affect the immunosuppressive effects of the TME [ 52 ].…”