Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells

Abstract

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and “normal” stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

“…Cancer‐associated fibroblasts stimulate the growth and proliferation of tumour cells. Matthew et al found that CAFs activated an immune checkpoint to suppress the function of T cells, which was mediated by the engagement of PDL2 and FASL Therefore, CAFs contribute to the suppression of anti‐tumour T cell response by regulating immune cells, such as promoting antigen‐specific T cells death . Cancer‐associated fibroblasts can also promote the invasion and metastasis of tumour cells.…”

The oncostatin M‐stromal cell axis in health and disease

“…iSCs are known to interact directly with several subsets of haematopoietic immune cells in the intestine and may play a role in maintaining T cell tolerance at steady state . Furthermore, stromal cell signatures are known to correlate with poor therapeutic response in colorectal cancer, although it is not clear whether this results from stromal cell suppression of protective T cell responses, as seen in other tumour types …”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…In this review, I consider direct contacts of CAFs with cells of the immune system, which, in my opinion, are important for strengthening and guiding the action of paracrine factors. CAFs can establish direct contacts with immune cells and affect the efficiency of checkpoint immunotherapy by means of the expression of co‐inhibitory receptor ligands). By now, such a possibility was experimentally demonstrated for PD‐L1 and/or PD‐L2 expression (Figure A).…”

“…However, most of these findings were made in in vitro experiments using isolated CAFs, and, therefore, require further studies to confirm the physiological significance of PD‐L1/L2 expression by CAFs for their immunosuppressive role in vivo . A recent paper, presents further evidence of the immuno‐inhibiting function of CAFs resulting from their direct interactions with immune cells. The authors show that CAFs can function as antigen presenting cells, able to absorb, process, and present on their surface tumor specific antigens complexed with MHC‐I proteins.…”

“…Neutralization of PD‐L2 or FASL reactivates the cytotoxic capacity of T cells in vitro and in vivo. Thus, CAFs might support T cell suppression within the tumor microenvironment by a mechanism dependent on immune checkpoint activation, hence representing another mechanism of T cell depletion and dysfunction within tumors …”