Thrombospondin-1:CD47 signaling contributes to the development of T cell exhaustion in cancer [scRNA_CD172KO]

T cell exhaustion, a hyporesponsive state of antigen-specific CD8+ T cells exhibiting elevated expression of multiple inhibitory surface receptors, is a major obstacle for the treatment of cancer. Current immune checkpoint blockade (ICB) therapies aimed at reinvigorating exhausted CD8+ T cells have demonstrated clinical effectiveness. However, not all cancer patients achieve long-term disease control due, at least in part, to the refractory nature of terminally exhausted CD8+ T cells to be functionally reinvigorated. Besides persistent antigen stimulation, the environmental sources and mechanisms that lead to CD8+ T cell exhaustion in cancer remain to be thoroughly characterized. Here, we show that the expression of CD47 [a.k.a. integrin-associated protein (IAP) and ‘‘don’t eat me’’ signal is upregulated in tumour-associated, exhausted CD8+ T cell compartments in both human and murine tumours. Our findings reveal a novel role of the extracellular matrix protein thrombospondin-1 (TSP-1) and CD47 in promoting T cell exhaustion. Engagement of TSP-1 with CD47 drives the upregulation of TOX and inhibitory immune checkpoint molecules and compromises the effector function of CD8+ T cells during tumour progression. Mechanistically, the interaction of TSP-1 with CD47 on CD+ T cells activates the calcineurin-NFAT signaling, thereby promoting TOX expression and the T cell exhaustion program in cancer.