A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy

Abstract

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden “stealth” antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5‐aza‐2′‐deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re‐expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re‐expression in xenografts in BALB/c‐nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T‐cells with a SPESP1‐derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1‐specific helper T‐cells were obtained; these cells produced interferon‐γ against HLA‐matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

A tumor metastasis‐associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity

“…The procedure for the expansion of peptide‐specific HTLs has been described in detail previously. 6 Briefly, monocytes and CD4 + T‐cells were purified from PBMCs using MACS microbeads for CD14 and CD4, respectively (Miltenyi Biotech). Monocytes were differentiated into DCs using GM‐CSF (50 ng/ml) and IL‐4 (1000 IU/ml).…”

“… 1 It is important to choose what types of tumor antigens make the immune system target tumor cells. Tumor antigens are categorized into several families 2 : (1) shared antigens, which are also expressed in normal cells such as MART‐1 and HER2 3 , 4 ; (2) tumor‐associated antigens, which are upregulated in tumor cells and weakly expressed in normal cells such as Survivin 5 ; (3) stealth antigens, which are epigenetically silenced in tumor cells such as SPESP1 6 ; and (4) neoantigens, which are encoded by mutated genes in tumor cells. 7 Because of their high immunogenicity, neoantigens are the most favorable targets in cancer immunotherapy.…”

Therapeutic Vaccination in Head and Neck Squamous Cell Carcinoma—A Review

“…On the other hand, tumor antigens can also be categorized as per their peculiar expression characteristics [ 29 ]. Some of the relevant classes in this regard include cancer/testis antigens (CTA) , which are restricted to reproductive organs (testis and placenta) but are overexpressed by cancer cells; oncoviral antigens , encoded by tumorigenic viruses and, thus, found only on virus-infected tumor cells; overexpressed/differentiation antigens , which are found in normal tissues but are significantly overexpressed in cancer cells; and mutated antigens (also known as neoantigens ), unique tumor antigens generated by a genetic mutation or alteration in transcription and found only in cancer cells [ 29 , 30 , 31 ]. Some of the prominent tumor antigens that have contributed greatly to the development of therapeutic vaccines, particularly in HNSCC, are the melanoma antigen-encoding gene (MAGE) ( CTA ), HPV-E6, E7 ( oncoviral ), Epstein–Barr virus (EBV)-related latent membrane protein (LMP)-2 ( oncoviral ), MUC-1, Wilm’s tumor (WT)-1, survivin, carcinoembryonic antigen (CEA) ( overexpressed and SHA ), and epidermal growth factor receptor(EGFR)-vIII (neoantigen ) [ 32 ].…”

Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1): A Promising Cancer Testis Antigen

“…This suggests that demethylation of genomic DNA can activate CTA expression. Later, it was gradually found that DNA demethylation could reactivate the expression of NY-ESO-1, KK-LC-1 and other CTAs genes [ 66 , 91 - 96 ]. Researchers found that the DNA methylation level is negatively correlated with the expression level of KK-LC-1.…”