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Cited by 151Immune cells in cancerCancer Cells and MetastasisTGF-β signaling in diseases

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Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy

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Raskov, Hans, Orhan, Adile, Gaggar, Shruti, Gögenur, Ismail·2021·Frontiers in Oncology
DOI 10.3389/fonc.2021.668731PMC PMC8172975
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Abstract

Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell communication within the TME plays a pivotal role in the evolution and progression of cancer. Cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) are major cell populations in the stroma of all solid tumors and often exert protumorigenic functions; however, the origin and precise functions of CAF and TAM are still incompletely understood. CAF and TAM hold significant potential as therapeutic targets to improve outcomes in oncology when combined with existing therapies. The regulation of CAF/TAM communication and/or their differentiation could be of high impact for improving the future targeted treatment strategies. Nevertheless, there is much scope for research and innovation in this field with regards to the development of novel drugs. In this review, we elaborate on the current knowledge on CAF and TAM in cancer and cancer immunotherapy. Additionally, by focusing on their heterogenous functions in different stages and types of cancer, we explore their role as potential therapeutic targets and highlight certain aspects of their functions that need further research.

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Crossref · 10.3389/fonc.2021.668731

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Figure 1 Major effects of CAF on immune cells in the tumor microenvironment. TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; IL, interleukin 6; GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, macrophage colony stimulating factor; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif ligand.
Figure 1 Major effects of CAF on immune cells in the tumor microenvironment. TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor; IL, interleukin 6; GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, macrophage colony stimulating factor; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif ligand.CC BY · PubMed Central
Figure 2 Kaplan–Meier curves depicting overall survival for high and low TAM densities across different cancer types. Overall survival curves, merged data, various cancers. Gastric cancer: Kaplan–Meier overall survival curves for gastric cancer patients with high TAM density (> 671 cells in five 400x microscopic fields; green dotted line) and low density (< 671 cells in five 400x microscopic fields; green solid line). The TAM density in the tumor tissue was negatively associated with overall survival [p=0.0073; (86)]. Breast cancer: Kaplan–Meier curves showing significant correlation (p<0.001) with overall survival according to the numbers of M2 TAM (CD163 high: yellow dotted line; CD163 low: yellow solid line) (87). Multiple myeloma: overall survival outcome based on low and high CD163 TAM (≤ 55 per high power microscopic field; dotted blue line) showing significant survival difference (p<0.001) (88). Ovarian cancer: Kaplan–Meier survival curves comparing high and low M1 (CD80)/M2 (CD163) ratios in patients with ovarian cancer. Patients with an M1/M2 ratio ≥ 1.4 (solid red line) showed a significantly higher overall survival (p=0.02) than those with an M1/M2 ratio < 1.4 (dotted red line) (89).
Figure 2 Kaplan–Meier curves depicting overall survival for high and low TAM densities across different cancer types. Overall survival curves, merged data, various cancers. Gastric cancer: Kaplan–Meier overall survival curves for gastric cancer patients with high TAM density (> 671 cells in five 400x microscopic fields; green dotted line) and low density (< 671 cells in five 400x microscopic fields; green solid line). The TAM density in the tumor tissue was negatively associated with overall survival [p=0.0073; (86)]. Breast cancer: Kaplan–Meier curves showing significant correlation (p<0.001) with overall survival according to the numbers of M2 TAM (CD163 high: yellow dotted line; CD163 low: yellow solid line) (87). Multiple myeloma: overall survival outcome based on low and high CD163 TAM (≤ 55 per high power microscopic field; dotted blue line) showing significant survival difference (p<0.001) (88). Ovarian cancer: Kaplan–Meier survival curves comparing high and low M1 (CD80)/M2 (CD163) ratios in patients with ovarian cancer. Patients with an M1/M2 ratio ≥ 1.4 (solid red line) showed a significantly higher overall survival (p=0.02) than those with an M1/M2 ratio < 1.4 (dotted red line) (89).CC BY · PubMed Central
Figure 3 Interplay between tumor, stromal, and immune cells. Depicts the interplay between cancer-associated fibroblasts (CAF), tumor-associated macrophages (TAM), growth factors, cytokines, interleukins, and immune cells in the tumor microenvironment (TME). CAF are the predominant cell type in the tumor stroma, contributing to the proliferative, pro-inflammatory, immunosuppressive, angiogenic, pro-invasive and pro-metastatic TME. They secrete various growth factors including TGF-β, vascular endothelial growth factor (VEGF), fibroblast growth factor 5, growth differentiation factor 15, and hepatocyte growth factor. CAF also produce cytokines and interleukins that may have both immunosuppressive and immuno-activating effects on various leukocytes, including CD8+ T cells, immunosuppressive regulatory T cells (Tregs) and macrophages. A subset of CAFs have myofibroblasts characteristics (myCAF) and play a major role in the development of the fibrotic stroma in the TME including the regulation of collagen fibre elongation. Growth factors and immunosuppressive cytokines produced by TAM enhance motility, intravasation, and invasion of tumor cells, while stimulating angiogenesis and suppressing T cell infiltration. Additionally, TGF‐β produced by TAMs activate immunosuppressive Tregs.
Figure 3 Interplay between tumor, stromal, and immune cells. Depicts the interplay between cancer-associated fibroblasts (CAF), tumor-associated macrophages (TAM), growth factors, cytokines, interleukins, and immune cells in the tumor microenvironment (TME). CAF are the predominant cell type in the tumor stroma, contributing to the proliferative, pro-inflammatory, immunosuppressive, angiogenic, pro-invasive and pro-metastatic TME. They secrete various growth factors including TGF-β, vascular endothelial growth factor (VEGF), fibroblast growth factor 5, growth differentiation factor 15, and hepatocyte growth factor. CAF also produce cytokines and interleukins that may have both immunosuppressive and immuno-activating effects on various leukocytes, including CD8+ T cells, immunosuppressive regulatory T cells (Tregs) and macrophages. A subset of CAFs have myofibroblasts characteristics (myCAF) and play a major role in the development of the fibrotic stroma in the TME including the regulation of collagen fibre elongation. Growth factors and immunosuppressive cytokines produced by TAM enhance motility, intravasation, and invasion of tumor cells, while stimulating angiogenesis and suppressing T cell infiltration. Additionally, TGF‐β produced by TAMs activate immunosuppressive Tregs.CC BY · PubMed Central

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Metadata

Authors
Raskov, H., Orhan, A., Gaggar, S., & Gögenur, I.
Affiliations
  • Zealand University Hospital Køge (DK)
  • University of Copenhagen (DK)
Corresponding author
Raskov, Hans
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2021-05-20
Volume
11
Pages
668731-668731
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2021.668731
PMC
PMC8172975
OpenAlex
W3163457197
Cited by
150
References
184
Citations by year
2026: 29 · 2025: 32 · 2024: 37 · 2023: 26 · 2022: 20 · 2021: 6
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
cancer-associated fibroblasts, tumor-associated macrophages, tumor microenvironment, cancer immunotherapy, tumor stroma, therapeutic target, intercellular communication, extracellular matrix

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