Single-cell meta-analyses reveal responses of tumor-reactive CXCL13⁺ T cells to immune-checkpoint blockade

Immune-checkpoint blockade (ICB) therapies represent a paradigm shift in the treatment of human cancers; however, it remains incompletely understood how tumor-reactive T cells respond to ICB across tumor types. Here, we demonstrate that measuring CXCL13 expression could effectively identify both precursor and terminally differentiated tumor-reactive CD8⁺ T cells within tumors. Applying this approach, we performed meta-analyses of published single-cell data for CXCL13⁺CD8⁺ T cells in 225 samples from 102 patients treated with ICB across five cancer types. We found that CXCL13⁺CD8⁺ T cells were correlated with favorable responses to ICB, and the treatment further increased such cells in responsive tumors. In addition, CXCL13⁺ tumor-reactive subsets exhibited variable responses to ICB in distinct contexts, likely due to different degrees of exhaustion-related immunosuppression. Our integrated analyses provide insights into mechanisms underlying ICB and suggest that bolstering precursor tumor-reactive CD8⁺ T cells might provide an effective therapeutic approach to improve cancer treatment.