HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors

Kwon Ho Song, Se Jin Oh, Suyeon Kim, Hanbyoul Cho, Hyo Jung Lee, Joon Seon Song, Joon Yong Chung, Eunho Cho, Jaeyoon Lee, Seunghyun Jeon, Cassian Yee, Kyung Mi Lee, Stephen M. Hewitt, Jae Hoon Kim, Seon Rang Woo, Tae Woo Kim

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Abstract

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.

Original languageEnglish
Article number562
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Song, K. H., Oh, S. J., Kim, S., Cho, H., Lee, H. J., Song, J. S., Chung, J. Y., Cho, E., Lee, J., Jeon, S., Yee, C., Lee, K. M., Hewitt, S. M., Kim, J. H., Woo, S. R., & Kim, T. W. (2020). HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors. Nature communications, 11(1), [562]. https://doi.org/10.1038/s41467-019-14259-y