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

Assaf Magen, Pauline Hamon, Nathalie Fiaschi, Leanna Troncoso, Etienne Humblin, Darwin D'souza, Travis Dawson, Matthew D. Park, Joel Kim, Steven Hamel, Mark Buckup, Christie Chang, Alexandra Tabachnikova, Hara Schwartz, Nausicaa Malissen, Yonit Lavin, Alessandra Soares-Schanoski, Bruno Giotti, Samarth Hegde, Raphael Mattiuz, Clotilde Hennequin, Jessica Le Berichel, Zhen Zhao, Stephen Ward, Isabel Fiel, Colles Price, Nicolas Fernandez, Jiang He, Baijun Kou, Michael Dobosz, Lianjie Li, Christina Adler, Min Ni, Yi Wei, Wei Wang, Namita T. Gupta, Kunal Kundu, Kamil Cygan, Raquel P. Deering, Alex Tsankov, Seunghee Kim-Schulze, Sacha Gnjatic, Ephraim Kenigsberg, Myron Schwartz, Thomas U. Marron, Gavin Thurston, Alice O. Kamphorst, Miriam Merad
bioRxiv doi:10.1101/2022.06.22.497216 (2022)


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 CD39hi TOXhi PD-1hi 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.