Cancer-Associated Fibroblast Mediated Inhibition of CD8+Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities

Simple Summary The ability of the immune system to kill tumour cells is a natural and extremely effective defence mechanism for fighting cancer. Cytotoxic-T-cells are a critical component of our immune system which function is to eliminate cancer cells. In some cancers, especially those with a rich tumour stroma, these cytotoxic-T-cells are unable to reach and kill the tumour cells. Cancer-associated fibroblasts are the most abundant cells in the tumour stroma and play a key role of the recruitment, infiltration and function of cytotoxic T-cells in the tumour, via several molecular mechanisms which we describe in this review. The tumour microenvironment (TME) is the complex environment in which various non-cancerous stromal cell populations co-exist, co-evolve and interact with tumour cells, having a profound impact on the progression of solid tumours. The TME is comprised of various extracellular matrix (ECM) proteins in addition to a variety of immune and stromal cells. These include tumour-associated macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells, as well as endothelial cells, pericytes and cancer-associated fibroblasts (CAFs). CAFs are the most abundant stromal cell population in many tumours and support cancer progression, metastasis and resistance to therapies through bidirectional signalling with both tumour cells and other cells within the TME. More recently, CAFs have been shown to also affect the anti-tumour immune response through direct and indirect interactions with immune cells. In this review, we specifically focus on the interactions between CAFs and cytotoxic CD8+ T cells, and on how these interactions affect T cell recruitment, infiltration and function in the tumour. We additionally provide insight into the therapeutic implications of targeting these interactions, particularly in the context of cancer immunotherapy.