Abstract
It has been demonstrated that DNA mutations generating neo-antigens are important for an effective immune response to tumors as evident from recent clinical studies of immune checkpoint inhibitors (ICIs). Further, it was shown that frameshift peptides (FSP) generated in tumors from insertions and deletions (INDELs) of microsatellites (MS) in coding region are a very good correlate of positive response to PD1 treatment. However, these types of DNA-sourced FSPs are infrequent in cancer. We hypothesize that tumors may also generate FSPs in transcription errors through INDELs in MS or by exon mis-splicing. Since there are a finite number of predictable sequences of such possible FSPs in the genome, we propose that peptide arrays with all possible FSPs could be used to analyze antibody reactivity to FSPs in patient sera as a FS neo-antigen screen. If this were the case it would facilitate finding common tumor neoantigens for cancer vaccines. Here we test this proposal using an array of 377 predicted FS antigens. The results of screening 9 types of dog cancer sera indicate that cancer samples had significantly higher antibody responses against FSPs than non-cancer samples. Both common reactive FSPs and cancer-type specific immune responses were detected. In addition, the protection of a common reactive FSP was tested in mouse tumor models, comparing to the non-reactive FSPs. The mouse homologs non-reactive FSPs did not offer protection in either the mouse melanoma or breast cancer models while the reactive FSP did in both models. The tumor protection was positively correlated to antibody response to the FSP. These data suggest that FSP arrays could be used for cancer neo-antigen screening.
Highlights
The research into, and clinical use of, checkpoint inhibitor immunotherapeutics (ICI) has pointed to the importance of neo-epitopes in an effective anti-tumor immune response[1,2,3]
We first described a new platform for screening potential cancer frameshift antigens that may be produced by RNA mis-processing. 377 frameshift antigens were represented in 830 frameshift peptides (FSP) peptides on the array
We selected non-reactive FSPs and a corresponding reactive FSP based on the array data
Summary
The research into, and clinical use of, checkpoint inhibitor immunotherapeutics (ICI) has pointed to the importance of neo-epitopes in an effective anti-tumor immune response[1,2,3]. An even more effective predictor are the frameshift neo-epitopes generated by microsatellite instability (MSI)[4,5,6] These peptides are produced when there is a failure to repair INDELs in microsatellites during DNA replication. These types of FSP neo-epitopes are infrequent in tumors. Personal cancer vaccines are largely focused on the much more frequent neo-epitopes produced by point mutations in the DNA. FS antigens appear to be important drivers of the positive immune response to tumors
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