Sperm-associated Antigens as Targets for Cancer Immunotherapy

Abstract

The identification of novel cancer-related and immunogenic proteins is still a challenge to be faced to improve antigen-specific tumor immunotherapy. The category of so-called cancer-testis (CT) antigens is one of the most perspective groups of proteins for anticancer immune response activation as normally they are expressed in immunoprivileged tissues and are immunogenic if aberrantly generated in tumors. The heterogeneous group of proteins called sperm-associated antigens (SPAG) might encompass novel CT antigens owing to their common expression in male germ cells, their ability to elicit immune response underlying infertility, and lately proposed oncogenic properties. We carried out a comprehensive analysis of the expression pattern in various normal and cancerous tissues and assessed the frequency of spontaneous humoral immune response against members of the SPAG group in cancer patients using phage-displayed antigen microarrays. Our results show that out of 15 analyzed SPAG genes only SPAG1, SPAG6, SPAG8, SPAG15, and SPAG17 are predominantly expressed in testis, whereas the others are ubiquitously expressed with only a testis-associated alternative splice variant of SPAG16. mRNA expression of SPAG1, SPAG6, and alternative splice variants of SPAG8, SPAG16, and SPAG17 was elevated in various tumors with frequencies ranging from approximately 10% to 70%. The upregulation of SPAG6 in lung and breast cancer was confirmed by immunohistochemical analysis of tumor and normal tissue microarrays. Cancer-associated spontaneous humoral immune response was detected against SPAG1, SPAG6, SPAG8, and a novel testis-specific splice variant of SPAG17 and ascribe these as novel CT antigens that potentially are applicable as immunotherapeutic targets and serologic biomarkers.

Overexpression of Testes-Specific Protease 50 (TSP50) Predicts Poor Prognosis in Patients with Gastric Cancer

“…Given the advantages of blood-testis barrier and the lack of human leukocyte antigen (HLA) class I expression on the surface of germ cells, immune therapies against CTAs do not cause autoimmune reaction. Therefore, discovery of novel cancer expressing CTAs has led directly to the development of antigen-specific cancer vaccines, providing a new opportunity for immune therapy of these tumors [34, 35]. In this regard, our results uncovered TSP50's potential to be a therapeutic target for gastric cancer as several other CTAs have been carried out for immunotherapy [35–37].…”

“…Many of the CTAs are specifically expressed in tumor cells and cancer stem cells and they are immunogenic [33, 34]. Given the advantages of blood-testis barrier and the lack of human leukocyte antigen (HLA) class I expression on the surface of germ cells, immune therapies against CTAs do not cause autoimmune reaction.…”

Comprehensive analyses of tumor immunity: implications for cancer immunotherapy

“…First, we examined 109 known cancer/testis (CT) genes [6, 30] for their association with immune components. MAGEA3 is an antigen that has been tested in cancer vaccines, although it failed to demonstrate improved progression-free survival in randomized non-small cell lung carcinoma clinical trials [31].…”

Chemotherapy-induced dynamic gene expression changes in vivo are prognostic in ovarian cancer

“…Expression levels of ALDH1A1 , ALDH5A1 , ALG13 , TMEM106B , SPAG16 and N4BP2L1 were also elevated in good prognosis clusters; however, their involvement in tumourigenesis is not established. Interestingly, elevated SPAG16 has been reported in various tumours (Siliņa et al , 2011), whereas N4BP2L1 maps in the region of BRCA2 (13q13.1). Downregulation of these genes coincides with the gradual loss of platinum sensitivity, as seen in the diminishing RTV reduction effect after day 7, and may be driving the switch from a responsive to a nonresponsive phenotype (Table 2).…”