The Immunogenic Potential of Recurrent Cancer Drug Resistance Mutations: An In Silico Study

Abstract

Cancer somatic mutations have been identified as a source of antigens that can be targeted by cancer immunotherapy. In this work, expanding on previous studies, we analyze the HLA-presentation properties of mutations that are known to drive resistance to cancer targeted-therapies. We survey a large dataset of mutations that confer resistance to different drugs and occur in numerous genes and tumor types. We show that a significant number of them are predicted in silico to be potentially immunogenic across a large proportion of the human population. Further, by analyzing a cohort of patients carrying a small subset of these resistance mutations, we provide evidence that what is observed in the general population may be indicative of the mutations’ immunogenic potential in resistant patients. Two of the mutations in our dataset had previously been experimentally validated by others and it was confirmed that some of their associated neopeptides elicit T-cell responses in vitro . The identification of potent cancer-specific antigens can be instrumental for developing more effective immunotherapies. In this work, we propose a novel list of drug-resistance mutations, several of which are recurrent, that could be of particular interest in the context of off-the-shelf precision immunotherapies such as therapeutic cancer vaccines.

Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance

“…We then calculated the Best Rank (BR) HLA class I presentation score of the mutation with respect to each HLA allotype in a list of 195 HLA-A/-B/-C allotypes total found among 1,261 individuals from the 1000 Genomes study (74). We defined the BR by predicting the eluted ligand likelihood percentile rank for each peptide associated to the mutation using the program NetMHCpan-4.0 (41) and taking the minimum elution rank among all peptides (75), excluding those with a wild-type NetMHC predicted Icore (76). We defined an individual's best rank (IBR) for a mutation m as the minimum BR of the mutation across all HLA class I allotypes of the individual.…”

Neoantigens in precision cancer immunotherapy: from identification to clinical applications

“…These mutations are perfect candidates for neoantigen screening. By investigating drug-resistant tumors, neoantigens can be discovered more efficiently and economically [100] . Cancer cells expressing such neoantigens are susceptible to the immunotherapies mentioned previously.…”

“…By investigating drug-resistant tumors, neoantigens can be discovered more efficiently and economically. [ 100 ] Cancer cells expressing such neoantigens are susceptible to the immunotherapies mentioned previously. Therefore, immunotherapies targeting neoantigens can be used to overcome drug resistance.…”

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

“…In particular, certain drugs could increase the expression of pre-existing TAA (e.g., 5-fluorouracil [ 113 ], see below) and others could be able to provoke the de novo generation of TNA (e.g., genotoxic antitumor agents [ 19 , 114 , 115 ]). The presence of neoantigens may also result from “spontaneous” tumor cell mutations responsible for drug resistance [ 116 , 117 ]. However, it should be stressed that antigen remodeling must not necessarily lead to favorable outcomes.…”