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

Liam Jenkins, Ute Jungwirth, Alexandra Avgustinova, Marjan Iravani, Adam Mills, Syed Haider, James Harper, Clare M Isacke

Research output: Contribution to journalArticlepeer-review

131 Citations (SciVal)

Abstract

Immune-checkpoint blockade (ICB) promotes antitumor 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 αCTLA4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathologic 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. The addition of wild-type, but not Endo180-deficient, CAFs in coimplantation 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 with tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors were 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.

SIGNIFICANCE: Paired syngeneic models help unravel the interplay between CAF and tumor immune evasion, highlighting the benefits of targeting fibroblast subpopulations to improve clinical responses to immunotherapy.

Original languageEnglish
Pages (from-to)2904-2917
Number of pages14
JournalCancer Research
Volume82
Issue number16
DOIs
Publication statusPublished - 16 Aug 2022

Bibliographical note

BBSRC iCASE studentship to ICR and AstraZeneca

Funding

This study was funded by a BBSRC iCASE studentship to ICR and AstraZeneca (BB/M016099/1 to L. Jenkins) and Programme Grants from Breast Cancer Now (S. Haider and C.M. Isacke) as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. This work represents independent research supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors thank Alan Melcher (ICR) for This study was funded by a BBSRC iCASE studentship to ICR and AstraZeneca (BB/M016099/1 to L. Jenkins) and Programme Grants from Breast Cancer Now (S. Haider and C.M. Isacke) as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. This work represents independent research supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors thank Alan Melcher (ICR) for insightful discussions, Suzanne Isabelle Sitnikova (AstraZeneca) for help with the design and running of the flow cytometry analyses, and the ICR Biological Services Unit and David Vicente for support with the animal work. The authors thank Dr. Ioannis Roxanis and Dr. Naomi Guppy in the Breast Cancer Now Toby Robins Research Centre Nina Barough Pathology Core Facility for pathology support, Dr. Richard Buus in the Breast Cancer Now Toby Robins Research Centre Pathway Profiling Team for running the NanoString panels, and Breast Cancer Now, working in partnership with Walk the Walk, for supporting the work of these two teams and also Dr. Syed Haider’s team.

Keywords

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cancer-Associated Fibroblasts
  • Cell Line, Tumor
  • Immune Checkpoint Inhibitors
  • Mice
  • Neoplasms
  • Tumor Microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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