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

Assaf Magen, Pauline Hamon, Nathalie Fiaschi, Brian Y. Soong, Matthew D. Park, Raphaël Mattiuz, Etienne Humblin, Leanna Troncoso, Darwin D’souza, Travis Dawson, Joel Kim, Steven Hamel, Mark Buckup, Christie Chang, Alexandra Tabachnikova, Hara Schwartz, Nausicaa Malissen, Yonit Lavin, Alessandra Soares-Schanoski, Bruno Giotti, Samarth Hegde, Giorgio Ioannou, Edgar Gonzalez-Kozlova, Clotilde Hennequin, Jessica Le Berichel, Zhen Zhao, Stephen C. Ward, Isabel Fiel, Baijun Kou, Michael Dobosz, Lianjie Li, Christina Adler, Min Ni, Yi Wei, Wei Wang, Gurinder S. Atwal, Kunal Kundu, Kamil J. Cygan, Alexander M. Tsankov, Adeeb Rahman, Colles Price, Nicolas Fernandez, Jiang He, Namita T. Gupta, Seunghee Kim-Schulze, Sacha Gnjatic, Ephraim Kenigsberg, Raquel P. Deering, Myron Schwartz, Thomas U. Marron, Gavin Thurston, Alice O. Kamphorst & Miriam Merad
Nature 2023


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+ TH”) and Granzyme K+ PD-1+ effector-like CD8+ T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+ 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+ TH 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+ TH control the differentiation of tumor-specific Progenitor exhasuted CD8+ T cells following ICB.