Novel T cell exhaustion gene signature to predict prognosis and immunotherapy response in thyroid carcinoma from integrated RNA-sequencing analysis

Abstract

Exhausted CD8⁺ T lymphocytes and tumor-associated macrophages play critical roles in determining cancer prognosis and the efficacy of immunotherapy. Our study revealed a negative correlation between exhausted CD8⁺ T lymphocytes and prognosis in thyroid carcinoma (THCA). Consensus clustering divided patients into two subgroups of exhaustion with different prognoses, as defined by marker genes of exhausted CD8⁺ T cells. Subsequently, we constructed an eight-gene prognostic signature, and developed a risk score named the exhaustion-related gene score (ERGS) to forecast both prognosis and immunotherapy response in THCA. Bulk RNA sequencing analysis revealed a higher prevalence of M2 macrophages, indicative of an immunosuppressive tumor microenvironment (TME), in the high-ERGS group. Single-cell RNA sequencing showed that SPP1⁺ macrophages and CD14⁺ monocytes infiltrations were positively associated with higher ERGS. Functionally, it was determined that SPP1⁺ macrophages exert an immunosuppressive role, while CD14⁺ monocytes were implicated in promoting tumor progression and angiogenesis. Analysis of cell-cell interactions between SPP1⁺ macrophages and T cells highlighted the activation of the SPP1-CD44 and MIF-CD74 axes, both of which could foster an immunosuppressive TME. Therapeutic strategies that target SPP1⁺ macrophages, CD14⁺ monocytes, and the SPP1-CD44 and MIF-CD74 axes may potentially improve the prognosis and amplify the immunotherapy response in THCA patients.

Keywords: Gene signature; Immunotherapy; Single-cell RNA-sequencing; T cell exhaustion; Thyroid carcinoma; Tumor-associated macrophage.