학술논문
Intratumoral dendritic cell–CD4+T helper cell niches enable CD8+T cell differentiation following PD-1 blockade in hepatocellular carcinoma
Document Type
Article
Author
Magen, Assaf; Hamon, Pauline; Fiaschi, Nathalie; Soong, Brian Y.; Park, Matthew D.; Mattiuz, Raphaël; Humblin, Etienne; Troncoso, Leanna; D’souza, Darwin; Dawson, Travis; Kim, Joel; Hamel, Steven; Buckup, Mark; Chang, Christie; Tabachnikova, Alexandra; Schwartz, Hara; Malissen, Nausicaa; Lavin, Yonit; Soares-Schanoski, Alessandra; Giotti, Bruno; Hegde, Samarth; Ioannou, Giorgio; Gonzalez-Kozlova, Edgar; Hennequin, Clotilde; Le Berichel, Jessica; Zhao, Zhen; Ward, Stephen C.; Fiel, Isabel; Kou, Baijun; Dobosz, Michael; Li, Lianjie; Adler, Christina; Ni, Min; Wei, Yi; Wang, Wei; Atwal, Gurinder S.; Kundu, Kunal; Cygan, Kamil J.; Tsankov, Alexander M.; Rahman, Adeeb; Price, Colles; Fernandez, Nicolas; He, Jiang; Gupta, Namita T.; Kim-Schulze, Seunghee; Gnjatic, Sacha; Kenigsberg, Ephraim; Deering, Raquel P.; Schwartz, Myron; Marron, Thomas U.; Thurston, Gavin; Kamphorst, Alice O.; Merad, Miriam
Source
Nature Medicine; 20230101, Issue: Preprints p1-11, 11p
Subject
Language
ISSN
10788956; 1546170X
Abstract
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+THwithin 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+THcontrol the differentiation of tumor-specific Progenitor exhasuted CD8+T cells following ICB.