Cancer/Testis Antigens as Biomarker and Target for the Diagnosis, Prognosis, and Therapy of Lung Cancer

Abstract

Lung cancer is the leading type of malignant tumour among cancer-caused death worldwide, and the 5-year survival rate of lung cancer patients is only 18%. Various oncogenes are abnormally overexpressed in lung cancer, including cancer/testis antigens (CTAs), which are restrictively expressed in the male testis but are hardly expressed in other normal tissues, if at all. CTAs are aberrantly overexpressed in various types of cancer, with more than 60 CTAs abnormally overexpressed in lung cancer. Overexpression of oncogenic CTAs drives the initiation, metastasis and progression of lung cancer, and is closely associated with poor prognosis in cancer patients. Several CTAs, such as XAGE, SPAG9 and AKAP4, have been considered as biomarkers for the diagnosis and prognostic prediction of lung cancer. More interestingly, due to the high immunogenicity and specificity of CTAs in cancer, several CTAs, including CT45, BCAP31 and ACTL8, have been targeted for developing novel therapeutics against cancer. CTA-based vaccines, chimeric antigen receptor-modified T cells (CAR-T) and small molecules have been used in lung cancer treatment in pre-clinical and early clinical trials, with encouraging results being obtained. However, there are still many hurdles to be overcome before these therapeutics can be routinely used in clinical lung cancer therapy. This review summarises the recent rapid progress in oncogenic CTAs, focusing on CTAs as biomarkers for lung cancer diagnosis and prognostic prediction, and as targets for novel anti-cancer drug discovery and lung cancer therapy. We also identify challenges and opportunities in CTA-based cancer diagnosis and treatment. Finally, we provide perspectives on the mechanisms of oncogenic CTAs in lung cancer development, and we also suggest CTAs as a new platform for lung cancer diagnosis, prognostic prediction, and novel anti-cancer drug discovery.

PRAME Is a Novel Target of Tumor-Intrinsic Gas6/Axl Activation and Promotes Cancer Cell Invasion in Hepatocellular Carcinoma

“…As CTAs have been linked to tumor progression by modulating epithelial cell plasticity [21][22][23][24][25]46], we analyzed whether PRAME contributes to an EMT phenotype in liver cancer. Therefore, we stratified publicly available HCC patient datasets according to PRAME expression and identified transcripts upregulated in PRAME-high patients including CTNND2, DLK1, KRT19, EPCAM, DKK1, AFP, MMP7 (Figure 2A).…”

“…High expression of PRAME is restricted to testis in adult tissues, while it is frequently augmented in malignant settings including melanoma or lung cancer, which adds PRAME to the family of cancer-testis antigens (CTAs) [19,20]. Interestingly, tumor-promoting functions were identified for some CTAs including e.g., HORMAD1 and NANOS3, which foster lung cancer invasion by EMT [21,22]. PRAME represses retinoic acid receptor (RAR) signaling by binding to RAR and hampering retinoic acid (RA)-induced receptor activation and target gene transcription [16].…”

Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer

“…To date, sparse information is available on anti-tumorigenic functions of CTAs with few studies reporting that TSAG10, RGS22, MAGE-A4 and SPANXA restrict tumorigenesis through the inhibition of tumor metabolic activity, proliferation and metastasis. 22 , 23 , 24 , 25 , 26 Traditionally, CTAs are thought to predominantly support cancer hallmarks such as sustaining proliferative signaling, resisting cell death, deregulating cellular energetics, activating invasion and metastasis, inducing angiogenesis, and genome instability and mutation. 5 , 6 , 7 , 8 , 12 , 27 , 28 For instance, members of the MAGE family have been shown to, in part through binding of the master tumor suppressor p53, promote tumor cell proliferation and cell cycle progression while inhibiting tumor cell survival.…”

Cancer testis antigen burden (CTAB): a novel biomarker of tumor-associated antigens in lung cancer

“…CTA-based biomarkers take advantage of this unique position of CTAs with respect to both the other, normally functioning cells in the body and the other aberrantly expressed genes found in tumor cells, and have potential applications in the diagnosis, monitoring, and treatment of cancer [ 18 – 21 ]. Given the restricted expression pattern and strong antigenicity of CTAs, they can serve as potential prognostic biomarkers and targets for immunotherapeutic interventions including ICIs, cancer vaccines, cellular and antibody-based therapies [ 18 , 22 ]. Individual CTAs have been previously used as biomarkers for prognosis and diagnosis in multiple tumor types [ 23 ].…”