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Oncoimmunology. 2018 Dec 24;8(3):1553478. doi: 10.1080/2162402X.2018.1553478. eCollection 2019.

A non-functional neoepitope specific CD8+ T-cell response induced by tumor derived antigen exposure in vivo.

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Biopharmaceutical New Technologies (BioNTech) Corporation, Mainz, Germany.
Experimental and Translational Oncology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Immunotherapy & Immunoprevention, German Cancer Research Center (DKFZ), and Molecular Vaccine Design, German Center for Infection Research (DZIF), Heidelberg, Germany.
TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Mainz, Germany.
JPT Peptide Technologies GmbH, Berlin, Germany.


Cancer-associated mutations, mostly single nucleotide variations, can act as neoepitopes and prime targets for effective anti-cancer T-cell immunity. T cells recognizing cancer mutations are critical for the clinical activity of immune checkpoint blockade (ICB) and they are potent vaccine antigens. High frequencies of mutation-specific T cells are rarely spontaneously induced. Hence, therapies that broaden the tumor specific T-cell response are of interest. Here, we analyzed neoepitope-specific CD8+ T-cell responses mounted either spontaneously or after immunotherapy regimens, which induce local tumor inflammation and cell death, in mice bearing tumors of the widely used colon carcinoma cell line CT26. A comprehensive immune reactivity screening of 2474 peptides covering 628 transcribed CT26 point mutations was conducted. All tested treatment regimens were found to induce a single significant CD8+ T-cell response against a non-synonymous D733A point mutation in the Smc3 gene. Surprisingly, even though Smc3 D733A turned out to be the immune-dominant neoepitope in CT26 tumor bearing mice, neither T cells specific for this neoepitope nor their T cell receptors (TCRs) were able to recognize or lyse tumor cells. Moreover, vaccination with the D733A neoepitope did not result in anti-tumoral activity despite induction of specific T cells. This is to our knowledge the first report that neoepitope specific CD8+ T cells primed by tumor-released antigen exposure in vivo can be functionally irrelevant.


CD8+ T cell cytotoxicity; CD8+ T cells; Neoepitopes; T cell priming; cancer immunotherapy

[Available on 2019-12-24]

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