Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies

Abstract

The introduction of a wide range of immunotherapies in clinical practice has revolutionized the treatment of cancer in the last decade. The majority of these therapeutic modalities are centered on reinvigorating a tumor-reactive cytotoxic T-cell response. While impressive clinical successes are obtained, the majority of cancer patients still fail to show a clinical response, despite the fact that their tumors express antigens that can be recognized by the immune system. This is due to a series of other cellular actors, present in or attracted towards the tumor microenvironment, including regulatory T-cells, myeloid-derived suppressor cells and cancer-associated fibroblasts (CAFs). As the main cellular constituent of the tumor-associated stroma, CAFs form a heterogeneous group of cells which can drive cancer cell invasion but can also impair the migration and activation of T-cells through direct and indirect mechanisms. This singles CAFs out as an important next target for further optimization of T-cell based immunotherapies. Here, we review the recent literature on the role of CAFs in orchestrating T-cell activation and migration within the tumor microenvironment and discuss potential avenues for targeting the interactions between fibroblasts and T-cells.

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

“…Finally, CAFs in the TME may also contribute to immunotherapy resistance by several mechanisms. Firstly, the release of immunosuppressive cytokines TGF-β and IL-6 by CAFs lead to reduced proliferation and trafficking capacity of antigen-presenting DCs, thereby impairing T cell priming against tumour antigens [ 145 , 148 ]. CAFs also directly upregulate immune checkpoint ligands on their surface, including PD-L1 and PD-L2 [ 149 , 150 ].…”

Endoglin: Beyond the Endothelium

“…The origin of CAFs is most probably heterogeneous and composed of activated local fibroblasts and bone marrow cells [130][131][132][133], or results from epithelial to mesenchymal transition (EMT) [134] and endothelial to mesenchymal transition (EndMT) [135,136]. These various sources might also lead to various CAF subsets, all with distinct roles in immune regulation, tumor progression, and metastasis [137,138]. Similar to its role in fibrosis, TGF-β is a main driver of CAF activation, mostly via the ALK5 signaling pathway.…”

Future Challenges in Cancer Resistance to Immunotherapy

“…These CAFs, due to their abundance and heterogeneity, can orchestrate the response to cancer immunotherapy via several mechanisms (Figure 1). Firstly, through the release of TGF-β and IL-6, CAFs suppress the proliferation and trafficking capacity of antigen-presenting DCs, thereby interfering with tumor-directed T cell priming [67]. Secondly, through the tight regulation of the local chemokine-and cytokine-gradient, CAFs limit the attraction of T cells to the TME [68,69].…”