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

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. Overall design: We performed 10X multiome for gene expression analysis, as well as chromatin assessments, from CD8+ T cells that were derived from tumors of mice treated with control or TAX2 peptides that disrupt the interaction between TSP-1 and CD47 during the course of tumor (B16 melanoma) progression. All CD8+ tumor-associated T cells were isolated for sort purification and then isolated for their nuclei for 10X multiome prep and sequencing. We mainly focus on their gene expression for comparison. Raw data are only provided for gene expression data.