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

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 ^hi TOX ^hi PD-1 ^hi CD8 ⁺ 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)