Liu et al. demonstrated that CXCL13 expression can effectively discriminate tumor-reactive T cells from bystander CD8+ T cell clones within tumors. Tumor-reactive CXCL13+CD8+ T cells showed precursor-like and terminally differentiated phenotypes, and their abundance significantly correlated with response to ICB across multiple cancer types. A similar correlation was observed with tumor-reactive blood cells. Higher CXCL13+CD4+ T cells also correlated with favorable response to ICB, and simultaneous measurement of CXCL13+ CD8+ and CD4+ T cell abundance achieved an overall predictive accuracy of ≥90% in multiple datasets.
Contributed by Shishir Pant
ABSTRACT: 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.
