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

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Immune-checkpoint blockade (ICB) shows promise in cancer treatment but has modest response rates in breast cancer.
• Cancer-associated fibroblasts (CAFs) contribute to tumor growth, metastasis, and immune suppression within the tumor microenvironment.

Purpose of the Study:

• To investigate the role of CAFs in mediating resistance to combination ICB therapy (αCTLA4 and αPD-L1).
• To explore the potential of targeting specific CAF subpopulations, like those expressing Endo180 (Mrc2), to improve immunotherapy outcomes.

Main Methods:

• Utilized paired syngeneic mouse mammary carcinoma models.
• Conducted transcriptomic, flow cytometric, and histopathologic analyses.
• Employed genetic deletion of Endo180 (Mrc2) in CAFs and coimplantation studies.

Main Results:

• CAF abundance correlated with insensitivity to ICB and an immunologically cold tumor microenvironment.
• Genetic deletion of Endo180 (Mrc2) reduced CAF populations and impaired tumor progression.
• Endo180-deficient CAFs did not restrict CD8+ T-cell infiltration, unlike wild-type CAFs.
• Tumors in Endo180 knockout mice showed increased CD8+ T-cell infiltration and enhanced ICB sensitivity.
• High MRC2 mRNA levels in human melanoma patients correlated with poor response to αPD-1 therapy.

Conclusions:

• CAF density and the expression of Endo180 (Mrc2) are associated with resistance to ICB in breast cancer models.
• Targeting Endo180-expressing CAFs can overcome immune evasion and improve responses to ICB.
• Therapeutic targeting of specific CAF subpopulations holds potential for enhancing immunotherapy efficacy in various cancers.