Tumor fibroblast-derived FGF2 regulates expression of SPRY1 in esophageal tumor-infiltrating T cells and plays a role in T cell exhaustion.

T cell exhaustion was initially identified in chronic infection in mice and was subsequently described in humans with cancer. Although the distinct signature of exhausted T cells in cancer has been well investigated, the molecular mechanism of T cell exhaustion in cancer is not fully understood. Using single-cell RNA sequencing, we report here that exhausted T cells in esophageal cancer were more heterogeneous than previously clarified. SPRY1 was notably enriched in two subsets of exhausted CD8+ T cells. When overexpressed, SPRY1 impaired T cell activation by interacting with CBL, a negative regulator of ZAP-70 tyrosine phosphorylation. Data from the Tumor Immune Estimation Resource revealed a strong correlation between FGF2 and SPRY1 expression in esophageal cancer. High expression of FGF2 was evident in fibroblasts from esophageal cancer tissue and correlated with poor overall survival. In vitro administration of FGF2 significantly upregulated expression of SPRY1 in CD8+ T cells and attenuated TCR-triggered CD8+ T cell activation. A mouse tumor model confirmed that overexpression of FGF2 in fibroblasts significantly upregulated SPRY1 expression in exhausted T cells, impaired T cell cytotoxic activity, and promoted tumor growth. Thus, these findings identify FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells in esophageal cancer.