Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses

Cui et al. (BioRxiv) DOI: 10.1101/2020.12.23.424168

 

Keywords

  • Tfh-B cell interactions

  • Tumor neoantigens

  • Lung adenocarcinoma

 

Main Findings

  • In this preprint, Cui, C. et al. demonstrate that the presence of Tfh and GC B cells associate with prolonged survival for lung adenocarcinoma patients

  • To delve into the functional role of Tfh and B cells in lung adenocarcinoma, they innovate a model called KP-HELLO in which tumors express a “HELLO” substrate composed of epitopes recognized by both T and B cells.

  • These KP- HELLO tumors could stimulate tumor-specific B and T cells to interact and develop into GC B cells and Tfh cells. These tumours had curbed growth as compared to KP tumors lacking this HELLO antigen.

  • In vivo knockout studies reveal that this tumor control was dependent on CD4+ T cells, CD8+ T cells, B cells, and ligands critical for B-CD4+ T cell interaction (ICOS and CD40L). Mice without these T-B cell interactions did not develop any Tfh cells and had reduced effector CD8+ T cell activity.

  • Since it is known Tfh cells produce IL-21 and B-Tfh cell interactions potentiate IL-21 production, they hypothesize that tumor growth control was induced by Tfh-derived IL-21 boosting effector CD8+ T cell anti-tumor immunity. 

  • They confirm that KP-HELLO tumor growth control was dependent on IL21R and that IL21RKO mice had reduced intra-tumoral effector CD8+ T cells. They found that the majority of IL21 in HELLO tumors came from Tfh cells, and that IL-21 producing Tfh cell development was dependent on tumor-specific B cell interaction with tumor-specific CD4+ T cells.

Limitations

  • From their study is not fully clear how and where Tfh cells provide IL-21 to CD8+ T cells. Further experiments are needed to see if inducing the HELLO antigen in KP lung tumors promote tumor-associated tertiary lymphoid structures with GCs and also to parse out if these Tfh-B cell interactions are occurring in draining lymph nodes.

  • Further experiments are needed to Tfh-derived IL-21’s effect on NK cells in addition to on CD8+ T cells.

  • While they were not able to examine GP33 antigen-specific CD8+ T cell responses against HELLO due to low numbers, it might be worthy of future investigation to see if these CD8+ T cells driving tumor control are specific to other epitopes within the HELLO protein and not GP33.

Significance/Novelty

  • Although presence of intra-tumoral Tfh and GC B cell has been observed to correlate with clinical benefit across multiple cancers, there was very little known about the role of Tfh cells or their interactions with B cells in cancer. Their study addressed this unexplored area and elucidated a role for tumor-specific B cell and CD4 T cell interactions in potentiating anti-tumor immunity.

  • The model they used to explore their question present a novel and easily applicable platform to investigate different aspects of B and T cell neoantigens (e.g. secreted/ membrane-bound/intracellular features)

  • The Tfh cell-B cell-IL21 axis they uncovered to be important for anti-tumor immunity may provide new potential therapeutic targets.

  • Their study had important implications for personalized neoantigen vaccines, supporting vaccines that include epitopes recognized by both B and T cells. Traditional metrics to identify candidate neoantigens focus on neoantigen abundance and MHC binding and T cell recognition, but this study supports that algorithms predicting B cell recognition could be useful too.

Credit 

Reviewed by Michelle Tran as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter.