Journal Article

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

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

2023

Overview

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. Response to anti-PD-1 in patients with hepatocellular carcinoma is associated with clonal expansion of intratumoral CXCL13 + CD4 + helper T cells and effector-like CD8 + T cells, and local dendritic cells enriched in expression of maturation and regulatory molecules help facilitate CD8 + T cell differentiation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/251 / 631/67/580 / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Carcinoma, Hepatocellular - drug therapy / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes / Cell Differentiation / CXCL13 protein / Dendritic cells / Dendritic Cells - pathology / Dendritic structure / Differentiation (biology) / Effector cells / Helper cells / Hepatocellular carcinoma / Hepatocyte nuclear factor 1 / Humans / Immune checkpoint inhibitors / Infectious Diseases / Interleukin 21 / Liver cancer / Liver Neoplasms - pathology / Lymphocytes / Lymphocytes T / Maturation / Metabolic Diseases / Molecular Medicine / Neurosciences / PD-1 protein / Priming / Programmed Cell Death 1 Receptor / T-Lymphocytes, Helper-Inducer / Tumors