Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.
|Publication status||Published - 2022 Dec|
Bibliographical noteFunding Information:
Tissue microarrays (TMAs) constructed from a cohort of 386 formalin-fixed, paraffin-embedded tumor specimens and matched nonadjacent normal specimens, have been described previously. The study samples from 178 cervical cancer patients and 126 cervical intraepithelial neoplasia (CIN) patients obtained by surgical resection in Gangnam Severance Hospital between 1996 and 2010 were histologically confirmed by a pathologist. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea (NRF-2017M3A9B8069610). Tissue samples were collected from patients who had signed informed consent form. This study was approved by the Institutional Review Board of Gangnam Severance Hospital (IRB# 3-2014-0184; Seoul, South Korea) and was additionally approved by the Office of Human Subjects Research at the National Institutes of Health. All procedures were conducted in accordance with the guidelines of the Declaration of Helsinki.
This work was supported by funding from the National Research Foundation of Korea (NRF-2020R1A2C1007157, NRF-2020R1A2B5B03095410 and NRF-2019R1A4A1029000).
© 2022, The Author(s).
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