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

  1. Assaf Magen
  2. Pauline Hamon
  3. Nathalie Fiaschi
  4. Leanna Troncoso
  5. Etienne Humblin
  6. Darwin D’souza
  7. Travis Dawson
  8. Matthew D. Park
  9. Joel Kim
  10. Steven Hamel
  11. Mark Buckup
  12. Christie Chang
  13. Alexandra Tabachnikova
  14. Hara Schwartz
  15. Nausicaa Malissen
  16. Yonit Lavin
  17. Alessandra Soares-Schanoski
  18. Bruno Giotti
  19. Samarth Hegde
  20. Raphaël Mattiuz
  21. Clotilde Hennequin
  22. Jessica Le Berichel
  23. Zhen Zhao
  24. Stephen Ward
  25. Isabel Fiel
  26. Colles Price
  27. Nicolas Fernandez
  28. Jiang He
  29. Baijun Kou
  30. Michael Dobosz
  31. Lianjie Li
  32. Christina Adler
  33. Min Ni
  34. Yi Wei
  35. Wei Wang
  36. Namita T. Gupta
  37. Kunal Kundu
  38. Kamil Cygan
  39. Raquel P. Deering
  40. Alex Tsankov
  41. Seunghee Kim-Schulze
  42. Sacha Gnjatic
  43. Ephraim Kenigsberg
  44. Myron Schwartz
  45. Thomas U. Marron
  46. Gavin Thurston
  47. Alice O. Kamphorst
  48. Miriam Merad
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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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