XLR, a novel immune escaping factor via P13K/AKT-mediated anti-apoptosis

다국어 초록 (Multilingual Abstract)

Tumor immune escape is one of the major obstacles facing cancer immunotherapy but the mechanisms involved remains poorly understood. To elucidate new mechanisms of immune escape, we generated a highly immune-resistant cancer cell line(TC-1 P3) by subjecting a susceptible cell line(TC-1/P0), a cervical cancer model expressing HPV16 E7 antigen. Successively, we isolated an immune resistant clone having a high expression of MHC class Ⅰ from TC-1 P3, and named TC-1 P3(A17). Through micro array analysis of TC-1 and TC-1 P3(A17), we finally identified a novel immune escaping factor, X-linked lymphocyte-regulated protein(XLR), as an immune resistant factor, which is up-regulated in TC-1 P3(A17),
It was found that XLR encodes a 30 KDa nuclear protein, expressed in lymphoid cells and in primary spermatocytes in a developmentally-regulated manner. Interestingly, we observed a significant expression of XLR protein in various murine tumor cell lines including TC-1 as well as a marked up-regulation of that in TC-1 P3(A17). To elucidate a role of XLR in immune resistance, XLR-overexpressed TC-1(TC-1/XLR) tumor cell line was generated by a retroviral vector system. TC-1/XLR cell line had a profound resistance to cytotoxic T lymphocyte(CTL)-induced apoptosis generated by Vac-Sig/E7/LAMP-1 immunization in vitro and in vivo as compared to TC-1/no insert. Interestingly, this XLR-mediated resistance strongly depended on PI3K/AKT signal pathway, which was confirmed by a pharmacological approach using various kinase inhibitors. Inversely, the activation of PI3K/AKT pathway by retroviral transfer of constitutively active form of AKT to TC-1 also increased its resistance against antitumor effects induced by immunization of Vac-Sig/E7/LAMP-1 or adoptive transfer of an E7specific T cell line. Most importantly, in combined therapy with an AKT inhibitor and an immunotherapeutic modality led to an enhanced anti-tumor effects against TC-1 P3(A17) in vivo, compared to either the immunotherapy or the inhibitor treatment alone.
Thus, our data suggest that XLR may represent a promising target to facilitate more favorable therapeutic efficacy of cancer immunotherapeutic modality against immune-resistant tumor cells