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 () and Tae Woo Kim ()
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Kwon-Ho Song: Korea University College of Medicine
Se Jin Oh: Korea University College of Medicine
Suyeon Kim: Korea University College of Medicine
Hanbyoul Cho: Yonsei University College of Medicine
Hyo-Jung Lee: Korea University College of Medicine
Joon Seon Song: National Institutes of Health
Joon-Yong Chung: National Institutes of Health
Eunho Cho: Korea University College of Medicine
Jaeyoon Lee: Northeastern University
Seunghyun Jeon: Korea University College of Medicine
Cassian Yee: The University of Texas MD Anderson Cancer Center
Kyung-Mi Lee: Korea University College of Medicine
Stephen M. Hewitt: National Institutes of Health
Jae-Hoon Kim: Yonsei University College of Medicine
Seon Rang Woo: Korea University College of Medicine
Tae Woo Kim: Korea University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14259-y

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