Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen
Creaney, J., Ma, S., Sneddon, S.A., Tourigny, M.R., Dick, I.M., Leon, J.S., Khong, A., Fisher, S.A., Lake, R.A., Lesterhuis, W.J., Nowak, A.K., Leary, S., Watson, M.W. and Robinson, B.W. (2015) Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen. OncoImmunology, 4 (7). e1011492.
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A key to improving cancer immunotherapy will be the identification of tumor-specific “neoantigens” that arise from mutations and augment the resultant host immune response. In this study we identified single nucleotide variants (SNVs) by RNA sequencing of asbestos-induced murine mesothelioma cell lines AB1 and AB1-HA. Using the NetMHCpan 2.8 algorithm, the theoretical binding affinity of predicted peptides arising from high-confidence, exonic, non-synonymous SNVs was determined for the BALB/c strain. The immunoreactivity to 20 candidate mutation-carrying peptides of increased affinity and the corresponding wild-type peptides was determined using interferon-γ ELISPOT assays and lymphoid organs of non-manipulated tumor-bearing mice. A strong endogenous immune response was demonstrated to one of the candidate neoantigens, Uqcrc2; this response was detected in the draining lymph node and spleen. Antigen reactive cells were not detected in non-tumor bearing mice. The magnitude of the response to the Uqcrc2 neoantigen was similar to that of the strong influenza hemagglutinin antigen, a model tumor neoantigen. This work confirms that the approach of RNAseq plus peptide prediction and ELISPOT testing is sufficient to identify natural tumor neoantigens.
|Publication Type:||Journal Article|
|Murdoch Affiliation:||School of Veterinary and Life Sciences|
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