Abstract 66: MHC class I polypeptide related sequence A as contributing factor to chemotherapy-induced resistance

Abstract

Abstract MHC class I polypeptide related sequence A (MICA) is a cell surface protein associated to tumor immunosurveillance activity, due to its ability to activate natural killer (NK) cells. Cleavage of MICA and generation of its soluble form (sMICA) has been described as an immunoevasion mechanism presented by aggressive tumors. In agreement with the role of MICA on tumor immunoevasion, recent studies correlated better prognosis for patients with higher levels of MICA expression in different types of cancer. Chemotherapeutic drugs are used to treat a great variety of malignant diseases. However, a fraction of patients under chemotherapy regimen stop responding to the treatment and develop recurrent tumors. We postulate that MICA can be a factor contributing to chemotherapy-induced resistance. To test our hypothesis, we tested the expression of MICA in prostate cancer-derived LNCaP and E006AA-hT cell lines were treated with bortezomib, a chemotherapeutic drug that inhibits proteasome activity. MTT cell viability assays showed that both cells had similar sensitivity to bortezomib, with IC50 of 10 nM and 8 nM for LNCaP and E006AA-hT, respectively. Flow cytometry analysis showed baseline difference in the cell fraction expressing surface MICA with 67% in LNCaP cells against 18% in E006AA-hT (p<000.1). Following treatment with bortezomib, the fraction of LNCaP cells expressing surface MICA increased 1.3-fold (p<0.01), while in the fraction of E006AA-hT cells expressing MICA yielded 2.3-fold increase (p<0.001). Baseline release rate of sMICA, assessed by ELISA analysis of culture supernatants, was 54 pg/ml/106cells for LNCaP and 5 pg/ml/106cells in E006AA-hT cells. Relative to baseline, sMICA release rate dropped 2-fold with bortezomib in LNCaP cells to 22 pg/ml/106cells (p<0.01). However, sMICA release rate in E006AA rose to 531 pg/ml/106cells (p<0.0001), more than 100-fold increase. Our findings show that, despite similar sensitivity to the killing effects of bortezomib in LNCaP and E006AA-hT, the release rate of sMICA in response to bortezomib is significantly distinct. These evidences lead us to propose that MICA is a contributing factor of resistance to chemotherapy, probably related to soluble MICA's immunoevasion properties. Further studies, testing cell specific ability of MICA's to affect cytotoxic activity in the context of chemotherapy-induced resistance will allow us to assess the value of this premise. This studies can open opportunities for new targeted immunotherapies, enhancing the innate immune system and avoiding the undesired effect of chemotherapy resistance. Citation Format: Marcelo Jun Sakiyama, Ingrid Espinoza, Deepak Kumar, Amit Reddy, Eldrin Bhanat, Krista Syrigos, Roya Gordji, Christian Gomez. MHC class I polypeptide related sequence A as contributing factor to chemotherapy-induced resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 66.