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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.