Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

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Abstract

Fibroblasts play an essential role in organogenesis and the integrity of tissue architecture and function. Growth in most solid tumors is dependent upon remodeling ‘stroma’, composed of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM), which plays a critical role in tumor initiation, progression, metastasis, and therapeutic resistance. Recent studies have clearly established that the potent immunosuppressive activity of stroma is a major mechanism by which stroma can promote tumor progression and confer resistance to immune-based therapies. Herein, we review recent advances in identifying the stroma-dependent mechanisms that regulate cancer-associated inflammation and antitumor immunity, in particular, the interactions between fibroblasts and immune cells. We also review the potential mechanisms by which stroma can confer resistance to immune-based therapies for solid tumors and current advancements in stroma-targeted therapies.

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TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Sanjeev Mariathasan, Shannon Turley, Dorothee Nickles … (2018)

Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC) 1–5 . However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here, we examined tumours from a large cohort of mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.

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A framework for advancing our understanding of cancer-associated fibroblasts

Erik Sahai, Igor Astsaturov, Edna Cukierman … (2020)

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

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Myeloid-derived suppressor cells as regulators of the immune system.

Dmitry I. Gabrilovich, Srinivas Nagaraj (2009)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

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Author and article information

Contributors

Ellen Puré:

ORCID: https://orcid.org/0000-0003-2107-3711

Guido Kroemer: Role: Reviewing Editor

Jeffrey Settleman: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 28 December 2020

Publication date Collection: 2020

Volume: 9

Electronic Location Identifier: e57243

Affiliations

[1]University of Pennsylvania PhiladelphiaUnited States

University of Paris Descartes France

Pfizer United States

Author information

Richard Lee Barrett https://orcid.org/0000-0002-2950-2106

Ellen Puré https://orcid.org/0000-0003-2107-3711

Article

Publisher ID: 57243

DOI: 10.7554/eLife.57243

PMC ID: 7769568

PubMed ID: 33370234

SO-VID: a1027910-c85c-42b0-9d31-6e0847809b6e

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 26 March 2020

Date accepted : 12 December 2020

Funding

No external funding was received for this work.

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Author impact statement Long under-appreciated, fibroblast biology is a key aspect of understanding how the immune system responds to tumors and may hold the key to improving immunotherapy in this tricky space.

ScienceOpen disciplines: Life sciences

Keywords: immunotherapy,fibroblast,cancer,tumor immunity,t-cell,macrophages

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: immunotherapy, fibroblast, cancer, tumor immunity, t-cell, macrophages

Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

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Cancer Immunotherapy

Most cited references 175

TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

A framework for advancing our understanding of cancer-associated fibroblasts

Myeloid-derived suppressor cells as regulators of the immune system.

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