Kurzfassung

Cancer immunotherapy has demonstrated remarkable efficacy by checkpoint modulation in a large variety of neoplasms. Therapeutic response correlates with the mutational load of the patient tumors, suggesting that neoantigens contribute to tumor rejection. However, a relevant proportion of patients with high mutational load do not benefit while some patients with low mutational burden do. This underscores the need for an improved understanding of underlying factors limiting the efficacy of...Cancer immunotherapy has demonstrated remarkable efficacy by checkpoint modulation in a large variety of neoplasms. Therapeutic response correlates with the mutational load of the patient tumors, suggesting that neoantigens contribute to tumor rejection. However, a relevant proportion of patients with high mutational load do not benefit while some patients with low mutational burden do. This underscores the need for an improved understanding of underlying factors limiting the efficacy of immune checkpoint therapy. To address this need, we will link an ImmuNEO module to the DKTK MASTER program that will include exome and transcriptome-sequenced patients on a pan-cancer basis who receive treatment with checkpoint modulators. Tumors from these patients will be used for peptide ligandome analyses, predictive in-situ biomarker analysis by immunohistochemistry, MALDI-TOF imaging mass spectrometry and RNA sequencing (RNAseq). T cells and TCR will be obtained from blood and tumor tissue and tested for neoantigen specificity and tumor reactivity. This project will provide a better understanding of the interplay between mutational signatures and the relevant components of the immune system aiming at biomarker discovery and the design of combinatorial treatment strategies based on the identified mechanisms of action.

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