Cancer Prevention by Vaccination against Induced Antigens

新抗原是由于基因突变、外源基因（如病毒蛋白）或替代抗原加工而产生的新获得和表达的“非自身”抗原。宿主免疫系统将这些与MHC分子一起出现在细胞表面的新肽识别为外源，发动免疫反应，并从体内清除表达新抗原的异常细胞。在肿瘤的发生和发展过程中，肿瘤积累了大量的基因突变，这些突变如果被翻译，就会产生新抗原。这些在癌症中表达的新抗原可以被宿主免疫系统监视和消除。最近使用免疫检查点抑制剂的癌症免疫治疗的临床成功已经清楚地表明，如果肿瘤来源的免疫抑制障碍被移除，宿主能够建立强大的抗肿瘤免疫反应。可以想象，在癌症预防环境中，针对新抗原的主动免疫可能更有效地激发有效的抗肿瘤免疫，在肿瘤免疫微环境中，来自肿瘤源性免疫抑制的干扰应该远不那么明显。

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.