Intratumoral dendritic cell-CD4⁺ T helper cell niches enable CD8⁺ T cell differentiation following PD-1 blockade in...

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13⁺CH25H⁺IL-21⁺PD-1⁺CD4⁺ T helper cells ("CXCL13⁺ T_H") and Granzyme K⁺ PD-1⁺ effector-like CD8⁺ T cells, whereas terminally exhausted CD39^hiTOX^hiPD-1^hiCD8⁺ T cells dominated in nonresponders. CD4⁺ and CD8⁺ T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1⁺TCF-1⁺ (Progenitor-exhausted) CD8⁺ T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8⁺ T cell differentiation occurs upon ICB. We found that these Progenitor CD8⁺ T cells interact with CXCL13⁺ T_H within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13⁺ T_H control the differentiation of tumor-specific Progenitor exhasuted CD8⁺ T cells following ICB.