Cancer testis antigen Sperm Protein 17 as a new target for triple negative breast cancer immunotherapy

Abstract

Breast carcinoma is a major health issue for millions of women. Current therapies have serious side effects, and are only partially effective in patients with metastatic tumors. Thus, the need for novel and less toxic therapies is urgent. Moreover, hormonal and antibody therapies effective in other subtypes are not effective in Triple Negative Breast Cancer (TNBC). Immunotherapeutic strategies directed against specific tumor-associated antigens (TAAs) and mediated by specific cytotoxic T lymphocytes (CTL) have been largely underexplored in this disease. Cancer-testis antigens (CTA) are a group of TAAs displaying the ideal characteristics of promising vaccine targets, i.e. strong immunogenicity and cancer specificity. The CTA, Sperm Protein 17 (SP17), has been found to be aberrantly expressed in different neoplasms, including ovarian and esophageal cancers, nervous system tumors and multiple myeloma, and has been suggested as a candidate target for immunotherapy.Here, we evaluated SP17 expression levels in breast cancer cell lines, invasive ductal breast carcinoma, including patients with TNBC, and adjacent non-neoplastic breast tissue, and determined whether SP17 was capable of generating SP17-specific cytotoxic T lymphocytes in vitro.We showed that SP17 is expressed in breast cancer cell lines and primary breast tumors and importantly in TNBC subtype, but not in adjacent non-tumoral breast tissue or unaffected tissues, except in male germinal cells. Furthermore, we detected specific anti-SP17 antibodies in patients’ sera and we generated SP17-specific, HLA class I-restricted, cytotoxic T lymphocytes capable of efficiently killing breast cancer cells.

Proteomic Differences in Feline Fibrosarcomas Grown Using Doxorubicin-Sensitive and -Resistant Cell Lines in the Chick Embryo Model

“…The possible connection between gametogenesis and cancer development has been previously suggested; for example, the expression of the synaptonemal complex protein 1 (SCP1), a protein selectively expressed during the meiotic prophase of the spermatocyte, has been reported in several tumour types, including: glioma, breast cancer, and melanoma, suggesting that it may contribute to genomic instability [ 59 ]. The sperm protein 17 (Sp17), which was primarily thought to be restricted only to developing spermatozoa and mature spermatids, has been shown to be expressed in breast cancer, multiple myeloma, epithelial ovarian cancer, and esophageal cancer, making it a potential candidate target for immunotherapy [ 60 , 61 ]. The MNS1 gene was shown to be down-regulated in an oxaliplatin-resistant human colon cancer cell line, and up-regulated in an oxaliplatin-sensitive human colon cancer cell line after continuous treatment with oxaliplatin for 24 h, suggesting its molecular role in chemoresistance [ 62 ].…”

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…CTAs are involved in cellular proliferation, migration/motility, colonization, and cell division in normal germ cells, while in cancer cells, CTAs have been implicated in sustenance of growth, maintaining nutrient and oxygen supply through the activation of angiogenesis, evading apoptotic cell death, increase in tissue invasiveness and metastasis, and development of resistance to anti-cancer drugs [214]. In breast cancer, CTAs, such as MAGE-1, AKAP4, NY-BR-1, CTAG1, BAGE1, MAGE-A10, SP17, NY-ESO-1, and MAGE-A, were found to play important roles in activating cell proliferation, inhibition of apoptosis, and promoting tissue invasion and metastasis [5,[215][216][217][218][219][220][221][222]. The CTA, AKAP4, in particular seems to be an interesting candidate for a serum-based diagnostic test for the early detection and diagnosis of breast cancer [221].…”

“…The CTA, AKAP4, in particular seems to be an interesting candidate for a serum-based diagnostic test for the early detection and diagnosis of breast cancer [221]. SP17, MAGE-A, NY-ESO-1, and MAGE-A10 on the other hand were more specifically associated with TNBCs [216,218,219]. There is but little evidence that could link the occurrence of diabetes to the expression of the CTAs, which can then be possibly used as diagnostic markers to link diabetes and the incidence of breast cancer or even a specific kind of breast cancer.…”

Challenges and perspectives in the treatment of diabetes associated breast cancer

“…Taylor et al has reported that, a vaccine directed against three CTAs-CTAG1, BAGE1 and MAGE-A10, can target two-thirds of breast cancers and can specifically target cytotoxic-T-lymphocyte responses [211]. Within the more stubborn TNBCs, when compared to other forms of breast cancer, CTA -SP17 is expressed in TNBCs [212]. NY-ESO-1 is expressed in a significant subset of TNBC subjects, leading to high humoral immune responses and therefore TNBC patients should benefit from targeted therapies against NY-ESO-1 [213].…”

“…The frequent occurrence of specific CTAs in breast cancers indicate a possibility to define and include new targets for therapeutic intervention [210,211]. Certain CTAs were expressed in the more stubborn TNBCs [212][213][214][215]. However, there is little evidence that links diabetes and breast cancer in terms of the expression and importance of CTAs in breast cancer.…”