The novel cancer-testis antigen A-kinase anchor protein 4 (AKAP4) is a potential target for immunotherapy of ovarian serous carcinoma

Abstract

Ovarian cancer is one of the neoplasms affecting the reproductive tract associated with high mortality rate because of limited therapeutic options and an elevated incidence of chemoresistance and recurrence. In this context, immunotherapy may constitute a promising approach to improve survival rates and clinical outcome, raising the need for specific target antigens. Cancer-testis antigens (CTAs) are considered promising candidates in this sense because they are aberrant expressed by various malignancies but not by non-transformed tissue, with the exception of testes. Here, we examined the expression and potential to promote humoral immune responses of a novel CTA, A-kinase anchor protein 4 (AKAP4), among 38 ovarian carcinoma patients. Our results reveal that AKAP4 was expressed at both the mRNA and protein levels in 89% (34/38) of ovarian carcinoma tissue specimens but not in 21 matched adjacent non-cancerous tissues. In addition, a humoral response against AKAP4 was detected in 58% (22/38) of ovarian carcinoma patients by ELISA. In particular, 65% (22/34) patients bearing an AKAP4-expressing tumor exhibited circulating anti-AKAP4 antibodies. Interestingly, the majority of specimens were categorized as ovarian serous adenocarcinoma and serous papillary carcinoma, of which 93% (28/30) and 100% (6/6), respectively, expressed AKAP4. A humoral response against AKAP4 was detected in 79% (19/24) and 67% (4/6) of ovarian serous adenocarcinoma and serous papillary carcinoma patients, respectively. The presence of circulating anti-AKAP4 antibodies suggests the AKAP4 is highly immunogenic in ovarian serous carcinoma patients. Our study lays the foundations for exploring AKAP4 as a potential target for the immunotherapy of ovarian cancer.

A novel cancer testis antigen target A-kinase anchor protein (AKAP4) for the early diagnosis and immunotherapy of colon cancer

“…Further, our data indicated that majority of CRC patients (84%, 168 of 200) demonstrated AKAP4 expression irrespective of stages and grades suggesting a possible role of AKAP4 in CRC. We have shown earlier that AKAP4 has been documented to be upregulated in breast cancer patients (85%), 12 epithelial ovarian carcinoma (EOC) patients (89%), 13 and cervix cancer patients (86%). 14 Moreover, other laboratories have also confirmed AKAP4 protein expression in 65% prostate cancer patients, 16 25% NSCLC patients, 17 and 42% multiple myeloma patients.…”

“…The RNA was reverse transcribed using a set of primers and High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Carlsbad, CA) as described earlier. 13 Following AKAP4 specific primers were used: AKAP4 Forward primer 5 0 -TGATACTACAAT-GATGTCTGATGAT-3 0 , AKAP4 Reverse primer 5 0 -GGAAC-TAGCAGCATCCTTGTAATCTTTATC-3 0 , b-actin was used as an internal control to check the quality of cDNA synthesis with following primers: b-actin Forward primer 5 0 -ATCTGGCAC-CACACCTTCTACAATGAGCTGCG-3 0 , b-actin Reverse primer 5 0 -CGTCATACTCCTGCTTGCTGATCCACATCTGC-3 0 . The PCR products were electrophoresed on 2% agarose gel and photographed under UV light in EC3 Imaging System (UVP, Upland, CA).…”

“…18 PKA has been proposed to be involved in majority of human tumors and malignant properties including cell proliferation, angiogenesis, and chemo-resistance. 12 This usefulness of AKAP4 as a biomarker and its potential as a candidate molecule for immunotherapy has been demonstrated in breast, 12 EOC, 13 cervix cancer. 14 However, the role of AKAP4 has not been studied in CRC so far.…”

“…AKAP4, a new member of CT antigen protein family, is expressed exclusively in male germ cells during spermatogenesis. 11 However, AKAP4 expression has also been demonstrated in various malignancies such as breast cancer, 12 epithelial ovarian cancer (EOC), 13 cervix cancer, 14 multiple myeloma, 15 prostate cancer, 16 and non-small cell lung carcinoma (NSCLC). 17 Owing to its expression in cancerous tissues and its potent immunogenicity, AKAP4 is considered as a promising biomarker and immunotherapeutic candidate.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…Its expression triggers humoral immune responses in ovarian cancer and is associated with malignant properties of cervical, breast and prostate cancer [138]. AKAP4 is currently analyzed as a potential target for cervical cancer immunotherapy [139,140]. The strong expression of AKAP4 in multiple myeloma led to its classification as cancer testes antigen [137].…”