Differential induction of T-cell tolerance by tumour fibroblast subsets

T-cell immunotherapy is now a first-line cancer treatment for metastatic melanoma and some lung cancer subtypes, which is a welcome clinical success. However, the response rates observed in these diseases are not yet replicated across other prominent solid tumour types, particularly stromal-rich subtypes with a complex microenvironment that suppresses infiltrating T cells. Cancer-associated fibroblasts (CAFs) are one of the most abundant and pro-pathogenic players in the tumour microenvironment, promoting tumour neogenesis, persistence and metastasis. Accumulating evidence is clear that CAFs subdue anti-tumour T-cell immunity and interfere with immunotherapy. CAFs can be grouped into different subtypes that operate synergistically to suppress T-cell function, including myofibroblastic CAFs, inflammatory CAFs and antigen-presenting CAFs, among other nomenclatures. Here, we review the mechanisms used by CAFs to induce T- cell tolerance and how these functions are likely to affect immunotherapy outcomes.