Neoantigens arise from somatic mutations and are exclusively expressed in cancer cells. These tumor-associated antigens are the ideal targets for immune recognition and attack. Derived by immune pressures, cancer cells down-regulate the recognizable targets on their surfaces and evolve into weakly immunogenic subclones [1]. It is generally believed that the loss of complex formation between neopeptide and major histocompatibility complex (MHC) in cancer cells is responsible for the acquired dysfunction of antigen processing and presentation [2].

Recently, Rosenthal et al. found that the hypermethylation of the promoter of neoantigen genes participated in the decreased cancer immunogenicity [3]. In this study, Rosenthal et al. analyzed immune infiltration statuses of untreated non-small cell lung cancer (NSCLC) patients by RNA-sequencing and tumor infiltrating lymphocyte (TIL) histopathology estimates [3]. The study showed that just 33% clonal neoantigens were ubiquitously expressed in every region of a given tumor [3]. Further investigation revealed that the proportion of ubiquitously expressed clonal neoantigens was significantly decreased in tumors with abundant TILs compared to tumors with scarce TILs (41% vs. 29%, P = 0.01) [3]. At the transcription level, the researchers observed immune pressure-caused neoantigen depletions [3]. Using the multi-region reduced representation bisulfite sequencing, it was detected that the genes carrying neoantigenic mutations harbored 11.4-fold increase in hypermethylation of promoters when compared to other genes (P = 0.00016) [3]. To verify whether this increased hypermethylation was neoantigen-specific or not, the researchers compare the methylation statuses between neoantigens and corresponding wild type genes. The results indicated that these non-expressed neoantigens were more likely to possess increased promoter methylation (odds ratio = 2.33, P = 0.045) [3].

These findings demonstrated that the neoantigen silencing was the result of immune pressures via promoter hypermethylation. The loss of neoantigens is a core event of immunoediting and immune evasion. Abundant neoantigens released from cancer cells initiate robust anti-cancer immune responses [4]. Then, professional antigen presentation cells (APCs) take in and process these neoantigens [4]. Subsequently, in peripheral lymphoid organs, the naïve T lymphocytes are primed and activated by APCs [4]. These activated T cells could migrate and infiltrate into tumors. Eventually, TILs recognize and kill cancer cells [4]. As a result, the release of more neoantigens propagate the anti-cancer immune response [4]. It is well accepted that cancer cells can adopt multiple manners to counteract immune clearance such as secreting anti-inflammation cytokines, upregulating immune checkpoint signals, counter-attacking TILs via increasing Fas ligand (Fas-L) expression, and disabling antigen presentation machinery (Fig. 1) [5, 6]. As the hallmark of cancer cells, neoantigens are generated as the by-products of accumulated somatic mutations [7]. Theoretically, tumor-associated neoantigens are ideal targets for immunotherapies with chimeric antigen receptor T cells (CAR-T) and bi-specific antibodies [8, 9], though in reality, resistance to these cancer neoantigen-targeted immunotherapies still remains a major challenge [10]. The results of Rosenthal et al. provide a novel perspective to the understanding of carcinogenesis and cancer evolution under immune pressure. Moreover, this study suggests that combination of hypomethylating agents with immunotherapy might offer double attack on neoantigen-rich cancers.

Fig. 1
figure 1

Promoter hypermethylation-mediated neoantigen downregulation leads to evasion of cancer immune response. Release of abundant neoantigens initiate anti-cancer immune response. Then, professional antigen presentation cells (APCs) take in and process these neoantigens. Subsequently, in peripheral lymphoid organs, the naïve T lymphocytes are primed and activated by APCs. These activated T cells migrate and infiltrate into tumors (TILs). These TILs recognize and destroy cancer cells. As a result, more neoantigens propagate the anti-cancer immune response. Under these immune pressure, cancer cells downregulate neoantigen expression by promoter hypermethylation and evolve into weakly immunogenic subclones

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