Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

ABSTRACT

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (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 ⁺ Th) 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 non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1 ⁺ TCF-1 ⁺ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13 ⁺ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13 ⁺ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.