Exploring Tumor Antigen Landscape during checkpoint immunotherapy

Individualized cancer vaccination strategies are emerging as promising anti-cancer treatment strategies. Most vaccination trials have focused on tumor neoantigens (caused by somatic mutations). However, it is well established that besides mutations, also alternative splicing events, expression of cancer-germline genes, expression of non-coding sequences, alternative start codons and other events can be sources of tumor antigens. To unbiasedly uncover the tumor antigens recognised by expanding tumour-reactive CD8+ T-cells in triple-negative breast cancer (TNBC) treated with checkpoint immunotherapy, we will apply a highly sensitive and high-throughput method 'TWISTAR'. This method allows the unbiased identification of a tumor antigen associated with a specific TCR sequence. Specifically, we will select 400 T-cell receptor sequences whose CD8+ T-cells expand during checkpoint immunotherapy based on their spatial localisation within the tumors. We will use TWISTAR to identify corresponding tumor antigens, and explore the genetic events contributing to these tumor antigens. Specifically, we will assess whether these tumor antigens are common in TNBC, distinguish which of these tumor antigens are already present before start of treatment, or are rather emerging during treatment, etc. Overall, we expect our project's findings to contribute to a better understanding of the tumor antigenicity within TNBC.