Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy

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Abstract

Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional diversity, which includes pro-tumorigenic roles in extracellular matrix remodeling, the suppression of anti-tumor immunity, and resistance to cancer therapy. Several methods for targeting CAFs to inhibit tumor progression and enhance anti-tumor immunity have recently been reported. While preclinical studies have shown promise, to date they have been unsuccessful in human clinical trials against melanoma, breast cancer, pancreas cancer, and colorectal cancers. This review summarizes recent and major advances in CAF-targeting therapies, including DNA-based vaccines, anti-CAF CAR-T cells, and modifying and reprogramming CAF functions. The challenges in developing effective anti-CAF treatment are highlighted, which include CAF heterogeneity and plasticity, the lack of specific target markers for CAFs, the limitations in animal models recapitulating the human cancer microenvironment, and the undesirable off-target and systemic side effects. Overcoming these challenges and expanding our understanding of the basic biology of CAFs is necessary for making progress towards safe and effective therapeutic strategies against cancers in human patients.

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Cancer statistics, 2022

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.

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Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

M Dominici, K Le Blanc, I. Mueller … (2006)

The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.

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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.