Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• T cell avidity

• CD8 T cells

• Tumor immunity

Main Findings

CD8 T cells play a crucial role in anti-tumor immunity by recognizing neoepitopes on cancer cells. The interaction between the T cell receptor (TCR) and the peptide-MHC I complex (pMHC I) on cancer cells is important for this recognition, but other factors such as TCR avidity, also play a role in determining the effectiveness of the immune response. In this study, Singhaviranon et al. found that low avidity T cells were more effective at conferring protection against tumors compared to high avidity T cells, using a murine model of MethA sarcoma expressing specific neoepitopes,  PDPRMUT and GTF2bMUT. High avidity T cells exhibited a transcriptionally exhausted phenotype, characterized by high expression of PD-1 and low expression of TIM3, LY108 and CX3CR1. RNA velocity analysis revealed distinct trajectories of low and high avidity T cells towards different exhausted phenotypes. Further analysis showed that low and high avidity T cells shared clonotypes, but differences in avidity were influenced by the expression levels of molecules like CD8a and TCRa. Low avidity T cells were also found to enhance response to immune checkpoint inhibitor therapy (PD-1 and CTLA-4 blockade). By developing an avidity score based on mouse transcriptomic data and applying it to human CD8 TILs (not antigen-specific) in various cancers, the researchers were able to predict patient responses to ICI therapy. These findings highlight the importance of T cell avidity and exhaustion status in regulating anti-tumor responses and provide insights into potential strategies for improving immunotherapy outcomes.

Limitations

• Although the authors identified two  neoepitopes in their previous publication that play a role in mediating tumor control, the findings presented herein are primarily focused on one neoepitope PDPRMUT. To make stronger conclusions and increase the impact of the paper, it would be important to describe similar mechanisms for other epitopes.

• Given the heterogeneity in T cell dysfunction, the findings linking T cell exhaustion and TCR avidity could be improved by describing exhausted populations based on the expression of multiple exhaustion markers.

• For reproducibility, it would be important to mention how avidity score was calculated and how it translates to the gene expression of human TILs. Does it also work for bulk antigen-non-specific mouse TILs in other models?

• The paper described one tumor model and it would be interesting to link their findings (or mention in the discussion) to other models.

• Upon publishing the manuscript, the code and raw data should be available.

Significance/Novelty

The preprint shows the link between T cell exhaustion status and avidity, and how it influences antitumor responses. One of the most exciting and clinically relevant findings shows that the “T cell avidity score” could be also applied to gene expression data from patients TILs in various cancers and predict the response to ICI therapy.

Credit

Reviewed by Aljawharah Alrubayyi and Alisa Iakupova as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.