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

Magen, A.; Hamon, P.; Fiaschi, N.; Troncoso, L.; Humblin, E.; D'souza, D.; Dawson, T.; Park, M. D.; Kim, J.; Hamel, S.; Buckup, M.; Chang, C.; Tabachnikova, A.; Schwartz, H.; Malissen, N.; Lavin, Y.; Soares-Schanoski, A.; Giotti, B.; Hegde, S.; Mattiuz, R.; Hennequin, C.; Le Berichel, J.; Zhao, Z.; Ward, S.; Fiel, I.; Price, C.; Fernandez, N.; He, J.; Kou, B.; Dobosz, M.; Li, L.; Adler, C.; Ni, M.; Wei, Y.; Wang, W.; Gupta, N. T.; Kundu, K.; Cygan, K.; Deering, R. P.; Tsankov, A.; Kim-Schulze, S.; Gnjatic, S.; Kenigsberg, E.; Schwartz, M.; Marron, T. U.; Thurston, G.; Kamphorst, A. O.; Merad,

doi:10.1101/2022.06.22.497216

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bioRxiv · 10.1101/2022.06.22.497216

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

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Abstract

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.

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Magen, A., Hamon, P., Fiaschi, N., Troncoso, L., Humblin, E., D'souza, D., Dawson, T., Park, M. D., Kim, J., Hamel, S., Buckup, M., Chang, C., Tabachnikova, A., Schwartz, H., Malissen, N., Lavin, Y., Soares-Schanoski, A., Giotti, B., Hegde, S., Mattiuz, R., Hennequin, C., Le Berichel, J., Zhao, Z., Ward, S., Fiel, I., Price, C., Fernandez, N., He, J., Kou, B., Dobosz, M., Li, L., Adler, C., Ni, M., Wei, Y., Wang, W., Gupta, N. T., Kundu, K., Cygan, K., Deering, R. P., Tsankov, A., Kim-Schulze, S., Gnjatic, S., Kenigsberg, E., Schwartz, M., Marron, T. U., Thurston, G., Kamphorst, A. O., Merad,. 2022-06-26. Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade. https://doi.org/10.1101/2022.06.22.497216

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