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Review
. 2021 Oct 11;20(1):131.
doi: 10.1186/s12943-021-01428-1.

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Xiaoqi Mao #  1   2   3   4 , Jin Xu #  1   2   3   4 , Wei Wang #  1   2   3   4 , Chen Liang  1   2   3   4 , Jie Hua  1   2   3   4 , Jiang Liu  1   2   3   4 , Bo Zhang  1   2   3   4 , Qingcai Meng  5   6   7   8 , Xianjun Yu  9   10   11   12 , Si Shi  13   14   15   16
Affiliations
Review

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Xiaoqi Mao et al. Mol Cancer. .

Abstract

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

Keywords: CAF-targeted therapy; Cancer; Cancer-associated fibroblasts; Cell–cell interaction; Immune suppression; Tumor immune microenvironment; Tumor microenvironment; Tumor-infiltrating immune cells.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The origins and related activating pathways of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). CAFs are derived from multiple cell types through the following distinct mechanisms: A Tissue-resident fibroblasts and quiescent stellate cells are converted into CAFs by the stimulation of modulators including transforming growth factor-beta (TGF-β), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2), stromal-derived factor-1 (SDF-1), reactive oxygen species (ROS) and insulin-like growth factor 1 (IGF-1) as well as the deficiency of vitamin A; B The trans-differentiation progress of mesenchymal stem cells (MSCs) into CAFs contain epithelial-mesenchymal transition (EMT) along with the recruitment and activation induced by various stimulating molecules such as TGF-β1, C–C chemokine ligand 2 (CCL2), C–C chemokine ligand 5 (CCL5), C-X-C chemokine ligand 12 (CXCL12) and tumor-derived exosomes; C Adipocytes together with pericytes and smooth muscle cells can transdifferentiate into CAFs by TGF-β1 and Wnt3a; D Endothelial cells are transformed into CAFs through endothelial-to-mesenchymal transition (EndMT); E Epithelial cells are transformed into CAFs through epithelial-to-mesenchymal transition (EMT); F Monocytes are transformed into CAFs through monocyte-to-myofibroblast trans-differentiation (MMT)
Fig. 2
Fig. 2
Crosstalk between cancer-associated fibroblasts (CAFs) and immune components in the tumor immune microenvironment (TIME). CAFs can orchestrate an immunosuppressive TME via interacting with the immune microenvironment in tumor. Through the secretion of multiple chemokines, cytokines and other effector molecules such as transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), C-X-C chemokine ligand 12 (CXCL12), C–C chemokine ligand 2 (CCL2), stromal-derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF) along with indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2), CAFs modulate immune cells-mediated antitumor immunity through the following pathways: Promoting the trans-differentiation or polarization of immune cells such as tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), mast cells (MCs), dendritic cells (DCs) and T lymphocytes into certain protumorigenic cell subsets; Facilitating the activities of immune inhibitory cells in terms of recruitment, activation and immunosuppressive effects including M2-type TAMs, N2-type TANs, regulatory DCs (rDCs), regulatory T(Treg) cells and myeloid-derived suppressor cells (MDSCs); Restricting the cytotoxic activity and cytokines production of effector immune cells like natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Notably, several infiltrating immune cells such as TAMs, TANs, MCs and DCs can in turn exert promoting effect on CAFs activation and function, thereby contributing to the formation of immune suppressive loops. Moreover, CAFs can also upregulate the expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1)/programmed death receptor ligand-1 (PD-L1) and cytotoxic T lymphocyte associate protein-4 (CTLA4)/B7 in both themselves and other cells in the TME to induce T-cells dysfunction. Meanwhile, CAFs are able to remodel extracellular matrix (ECM) to facilitate immune suppression through the production of fibronectin, collagen and metalloproteinases (MMPs) as well as the activation focal adhesion kinase (FAK) signaling pathway. Finally, immune checkpoint molecule overexpression on CAF surface as well as matrix deposition around would inhibit CAF apoptosis and facilitate their activation and function
Fig. 3
Fig. 3
Major CAF-targeted immunotherapeutic strategies. There are three main approaches against cancer-associated fibroblasts (CAFs) and their associated molecules for immunotherapy: A Through the immunotherapies or transgenic technologies that targeting CAF markers such as fibroblast activation protein (FAP), alpha-smooth muscle actin (α-SMA) and platelet-derived growth factor receptors (PDGFR), CAFs can be directly depleted and consequently enhance immune response in the tumor microenvironment (TME); B CAF activation and function can be suppressed by inhibiting their crucial effector molecule or signaling pathways such as vitamin A, transforming growth factor-beta (TGF-β), interleukin-6 (IL-6) together with Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway, C–C chemokine ligand 2 (CCL2)-C–C chemokine receptor (CCR2) signaling axis and C-X-C chemokine ligand 12 (CXCL12), thereby restricting the immune suppression induced by CAFs in the TME; C CAF-derived matrix proteins such as tenascin-C (TNC), hyaluronan (HA) and matrix metalloproteinases (MMPs) as well as related fibrosis-activated signaling pathways, like focal adhesion kinase (FAK) signaling pathways, are the ideal targets to effectively restrict extracellular matrix (ECM) remodeling
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