Cancer immunotherapy has emerged as a promising cancer treatment. However, the presence of immune-refractory tumor cells limits its clinical success by blocking amplification of anti-tumor immunity. Previously, we found that immune selection by immunotherapy drives the evolution of tumors toward multi-modal resistant and stem-like phenotypes via transcription induction of AKT co-activator TCL1A by NANOG. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and multi-aggressive properties of immune-edited tumor cells by identifying HSP90AA1 as a NANOG transcriptional target. Furthermore, we demonstrate that HSP90A potentiates AKT activation through TCL1A-stabilization, thereby contributing to the multi-aggressive properties in NANOGhigh tumor cells. Importantly, HSP90 inhibition sensitized immune-refractory tumor to adoptive T cell transfer as well as PD-1 blockade, and re-invigorated the immune cycle of tumor-reactive T cells. Our findings implicate that the HSP90A-TCL1A-AKT pathway ignited by NANOG is a central molecular axis and a potential target for immune-refractory tumor.
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Tissue samples and immunohistochemistry. Tissue microarrays (TMAs) containing four 1.0-mm-diameter cores retrieved from 483 formalin-fixed, paraffin-embedded tumor specimens, and matched nonadjacent normal specimens, were previously described16. The study subjects were compromised of 169 cervical cancers and 314 cervical intraepithelial neoplasia (CIN) patients who underwent surgical resection in Gangnam Severance Hospital between 1996 and 2010. Some of the paraffin blocks were provided by the Korea Gynecologic Cancer Bank through 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 (Seoul, South Korea), and all procedures were conducted in accordance with the guidelines of the Declaration of Helsinki.
This work was funded by the National Research Foundation of Korea (NRF-2016R1A6A3A11933484, NRF-2017R1A2A1A17069818, and NRF-2019R1A4A1029000).
© 2020, The Author(s).
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)