Targeting CTCFL/BORIS for the immunotherapy of cancer

Abstract

Cancer vaccines have great potential in the fight against metastatic malignancies. Current anti-tumor immunotherapy is hindered by existing tolerance to tumor-associated antigens (TAA) and tumor escape using various mechanisms, highlighting the need for improved targets for immunotherapy. The cancer-testis antigen CTCFL/BORIS was discovered 16 years ago and possesses all features necessary for an ideal TAA. Recently CTCFL/BORIS has received additional attention as a target expressed in cancer stem cells (CSC). These cells drive tumor growth recurrence, metastasis, and treatment resistance. CTCFL/BORIS silencing leads to senescence and death of CSC. Therefore, an immunotherapeutic strategy that targets CTCFL/BORIS may lead to the selective destruction of CSC and potential eradication of metastatic disease. The high immunotherapeutic potential of CTCFL/BORIS antigen was shown in a stringent 4T1 mouse model of breast cancer. Using these highly metastatic, poorly immunogenic carcinoma cells inoculated into T-helper2 prone mice, we showed that DC fed with recombinant CTCFL/BORIS as an immunogen inhibited tumor growth and reduced the number of metastases in distant organs. About 20% of CTCFL/BORIS immunized animals were tumor free. 50% of animals remained metastasis free. Those having metastasis showed at least tenfold fewer metastases compared to controls. In a rat model of breast cancer, we showed that alphavirus-based CTCFL/BORIS immunotherapy was capable of cancer elimination as we were able to cure 50% of animals. Based on the above data, we believe that translation of CTCFL/BORIS-targeting immunotherapeutic strategies to the clinic will provide new avenues for improving survival of breast cancer patients with advanced metastatic disease.

Keywords: CITIM 2017; CTCF functional interference; CTCFL/BORIS; Cancer immunotherapy target; Cancer stem cells (CSC); Mouse and rat breast carcinoma models.

Fig. 1

Normal expression of BORIS in different organs and tissues. a–c independent RNA-seq data from different projects (indicated on top of each panel) collected from multiple individuals of various ages and genders. Note that a and c show data in reads per kilobase of transcripts per million of mapped reads (RPKM) while b data are shown in transcripts per million (TPM). d RNA CAGEs, essentially transcription start sites showing only capped RNA. e Antibody staining data

Fig. 2

a In normal cells, CTCF, depicted as a red circle, is an activator of p53, p14 ARF, p16Ink and other tumor suppressor genes which respond to signals from neighboring cells to stop growth. However, in cancer, CTCF is substituted by CTCFL/BORIS, depicted as a blue circle, shutting down the transcription of these tumor suppressor genes through activation of anti-sense transcripts. The direction of active transcription is shown with a red arrow, and the direction of inactive transcription is shown with a black arrow. Without activation of tumor suppressor genes, cells can grow out of control and become cancerous. b Same color code as in a. In normal cells, CTCF is a suppressor of c-MYC, hTERT, PIM1 and other oncogenes. However, in cancer cells, CTCFL/BORIS may replace CTCF and activate these genes. In these conditions, cells can grow out of control and become cancerous