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 CD39 hi TOX hi PD-1 hi 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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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/6830524.

    Review of: Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade." BioRxiv. DOI: https://doi.org/10.1101/2022.06.22.497216

     

    This preview was written by Yip Ming Tsun Sophronia , a trainee in the Rio Sugimura lab at the University of Hong Kong as a part of her training in studying cancer immunotherapy.

     

    Summary:

    To investigate the detailed molecular and cellular mechanisms involved in triggering an effective anti-tumor response after PD-1/PD-L1 blockade in tumors, this paper study the TME composition of surgically-resected tumor lesions from HCC patients treated with neoadjuvant PD-1 blockade. They compared the TME composition between T cell-rich non-responder patients and T cell-rich responder patients. By using scRNA-seq and single-cell T cell receptor sequencing (scTCRseq), they found out that PD-1high effector-like CD8 T cells and CXCL13+ T helper cells were clonally expanded in tumors of responders when compared to non-responders, while PD-1high terminally exhausted CD8 T cells and Tregs were clonally expanded preferentially in tumors of non-responders. They later identify a cellular triad composed of mregDC, PD-1high  CD8 progenitor T cells, and CXCL13+ T helper cells in tumors of responders using multiplex imaging analysis and proposed possible interactions between the triad using receptor-ligand mapping, concluding that these interactions drive local differentiation of PD-1high CD8 progenitor T cells into effector like phenotype instead of terminally exhausted phenotype upon PD-1 blockade. 

     

    Major comments

     

    Strengths:

    1. New perspective on the role of mregDC in PD-1 blockade responsiveness

    -In the past, the responsiveness of PD-1 blockade therapy is often determined by the abundance of T cells in tumor sites but emerging evidence also suggested that a proportion of non-responders are also rich in T cells in tumor sites. This paper showed a comprehensive comparison between T cell-rich responders and non-responders. They proposed a novel mechanism of the role of mregDC and its interactions with a specific subset of T cells attributed to the anti-tumor effect after PD-1 blockade. This finding could target molecules to enhance mregDC interaction with the T cells in the triad that could enhance the responsiveness of PD-1 blockade therapy in patients.

     

    2. Multiple angles to prove that PD-1high CD8 T cells and CXCL13+ Th are important in determining the responsiveness of PD-1 blockade

    -The authors conducted multiple experiments to support this claim, firstly scRNA-seq to show that PD-1high CD8 T cells and CXCL13+ Th were enriched in the tumour site of responders when compared to non-responders. They also used scTCRseq and compared the quantity of T cell clones before and after treatment to show that they expand locally and clonally upon PD-1 treatment. Apart from quantitative results, BaseScope TCR imaging analysis showed the spatial expansion of PD-1high CD8 T cells and CXCL13+ Th on the sample.

    Moreover, the author also showed a correlation between the cellular abundances of CXCL13+ Th and PD-1high effector-like CD8 T cells, evidence for the later discussion of the possible positive regulation between these 2 cell types in the cellular triad. These data provide solid evidence that these 2 groups of T cells play a significant role in PD-1 blockade responsiveness.

     

    To be improved:

     

    1. Missing link between how PD-1 blockade affects mregDC phenotype and its interactions with CXCL13+ Th, and PD-1hi CD8 T cells.

    -They proposed possible interactions between mregDC, CXCL13+ Th, and PD-1hi CD8 T cells by receptor-ligand mapping and how their interactions lead to a favorable response in patients. However, they did not show why PD-1 blockade in responders enhances the formation of the triad and their interactions.

     

    2. Direct evidence of mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells.

    -Although they conclude that the interaction between mregDC and CXCL13 T helper enhances the differentiation of PD-1hi CD8 T progenitors to an effector, direct evidence is missing. They could validate that with co-culture experiments and perform transcriptome analysis on CD8 T cells, to see whether the differentiation to effector phenotype is enhanced in the presence of mregDC and CXCL13 Th cells.

     

    3. Which specific receptor-ligand interactions are enhanced after PD-1 blockade?

    -They used receptor-ligand mapping to identify the expression of candidate molecules that might promote interactions between triads to account for the enhanced anti-tumor effect after PD-1 blockade. They proposed the possible role of CH25H, LTB, CD40L, and XCL1 as causative factors in the triad. The inhibitors of these molecules could validate their roles in a co-culture setting.

     

    Minor comments  

    -Why are B cells also enriched within the triad?

    -Co-culture experiments to dissect the molecular mechanisms of how the cellular triad interacts with each other to support the hypothesis in the discussion part

     

     

    Overall:

    The former part of the paper show really convincing results of the enrichment of PD-1high CD8 T cells and CXCL13+ Th within tumor sites in responders, but mechanisms on the cellular triad could be improved. Relating how PD-1 blockade leads to the formation of the triad and their interactions, and identification of causative factors that account for the enhanced anti-tumor effect will enhance the impact of the manuscript.

  2. Version published to 10.1101/2022.06.22.497216v1 on bioRxiv