Researchers led by Ludwig Weill Cornell’s Chien-Huan Weng and Co-directors Taha Merghoub and Jedd Wolchok reported in a November issue of Nature Immunology an underappreciated mechanism by which anti-cancer T cells in tumors are pushed into functional exhaustion and showed in preclinical studies how it might be sabotaged to boost the efficacy of cancer immunotherapy. They found that thrombospondin-1 (TSP-1), an extracellular matrix protein, can bind CD47, a receptor on the surface of CD8+ T cells (CTLs), to drive their functional exhaustion. The study stemmed from observations made several years ago in Jedd and Taha’s lab that CD8+ T cells bearing the markers of exhaustion also express CD47 at noticeably high levels. The researchers discovered that TSP-1 engagement of CD47 activates the calcineurin-NFAT signaling pathway and drives the expression of TOX, a master regulator of T cell exhaustion, along with other markers of exhaustion. Disruption of TSP-1 binding to CD47 by a small peptide snapped exhausted anti-tumor T cells out of their functional stupor. This revived the cell-killing capabilities of CTLs, improved their infiltration into tumors—even into “cold” tumors that ordinarily harbor few CTLs—and improved the efficacy of PD-1 blockade, extending survival in mouse models of cancer.
Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer
Nature Immunology, 2025 November 17