Neoantigens are newly acquired and expressed ?non-self? antigens arising as a consequence of gene mutations, exogenous genes (e.g. viral proteins), or alternative antigen processing. The host immune system recognizes these neo-peptides presented with MHC molecules on the cell surface as foreign, mount immune responses, and eliminate the neoantigen-expressing aberrant cells from the body. During tumor development and progression, tumors accumulate numerous gene mutations, which, if translated, give rise to neoantigens. These neoantigens expressed in cancers can be targeted by the host immune system for surveillance and elimination. Recent clinical successes of cancer immunotherapy with immune checkpoint inhibitors have clearly demonstrated that the host is capable of mounting robust antitumor immune responses if the obstacle of tumor-derived immune suppression is removed. It is conceivable that effective antitumor immunity may be more efficiently elicited by active immunization against neoantigens in the cancer prevention setting, where interference from tumor-derived immunosuppression should be far less pronounced in the tumor-immune microenvironment. One of the major challenges of developing effective cancer vaccines is the selection of target antigens. Tumor-associated neoantigens can be vastly heterogenous and immune responses are restricted by MHC molecules. Their expression levels also vary among different neoantigens. Because of the intra- and inter-individual heterogeneity of tumor-associated neoantigens and the diversity of immune responses that are determined by HLA alleles, it is highly challenging to develop broadly applicable cancer vaccines targeting common neoantigens for different individuals. Gilboa and his colleagues have previously shown that small interfering RNA (siRNA)-mediated inhibition of nonsense-mediated mRNA decay in tumor cells resulted in the expression of new antigenic determinants and their immune-mediated rejection in preclinical models of cancer. However, a significant proportion of the induced neoepitopes were found to have come from mutated genes that were not shared by all tumor cells, thus limiting the utility of this approach as an immunotherapeutic modality. Immune-mediated targeting of tumor cells that express induced neoantigens may also be accomplished by the downmodulation of the classical MHC class-I antigen presentation machinery, such as the transporter associated with antigen presentation (TAP) or endoplasmic reticulum aminopeptidase associated with antigen processing (ERAP1 or ERAAP) proteins, which leads to the upregulation of alternative antigen processing pathways and presentation of neoepitopes. Peptides arising as a result of alternative antigen processing pathways are derived from non-mutated housekeeping proteins, but normally ?absent?, and therefore can be considered as neoantigens shared by all cells deficient in the classical MHC-I antigen presentation pathway. These peptides, referred to as T cell epitopes associated with impaired peptide processing (TEIPP), can trigger T cell responses against tumor cells that are deficient in antigen processing. Temporary downmodulation of TAP by targeted delivery of specific siRNA to precancerous and cancerous cells, using, for example, nucleolin-targeting aptamer, can result in the transient induction of ?clonal neoantigen? expression, which may elicit neoantigen-specific immune responses that are associated with antitumor efficacy. This siRNA-based downmodulation of the classical antigen presentation pathway can be used as a broadly applicable immunoprevention strategy in high risk cohorts such as individuals with premalignant diseases or those with hereditary cancer syndrome (e.g. BRCA1/2 mutation carriers). The current study aims to evaluate the durable antitumor efficacy of cancer vaccines against TAP-modulation induced neoantigens in preclinical models of BRCA1-driven mammary cancers.
