دورية
Intratumoral dendritic cell–CD4+T helper cell niches enable CD8+T cell differentiation following PD-1 blockade in hepatocellular carcinoma
| العنوان: | Intratumoral dendritic cell–CD4+T helper cell niches enable CD8+T cell differentiation following PD-1 blockade in hepatocellular carcinoma |
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| المؤلفون: | 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 |
| المصدر: | Nature Medicine; 20230101, Issue: Preprints p1-11, 11p |
| مستخلص: | 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 10788956 1546170X |
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| DOI: | 10.1038/s41591-023-02345-0 |