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

doi:10.1038/s41467-019-14259-y

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

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

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 NANOG^high 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 language	English
Article number	562
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14259-y
Publication status	Published - 2020 Dec 1

Bibliographical note

Funding Information:
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.

Funding Information:
This work was funded by the National Research Foundation of Korea (NRF-2016R1A6A3A11933484, NRF-2017R1A2A1A17069818, and NRF-2019R1A4A1029000).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-14259-y

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), Article 562. https://doi.org/10.1038/s41467-019-14259-y

Song, KH, Oh, SJ, Kim, S, Cho, H, Lee, HJ, Song, JS, Chung, JY, Cho, E, Lee, J, Jeon, S, Yee, C, Lee, KM, Hewitt, SM, Kim, JH, Woo, SR & Kim, TW 2020, 'HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors', Nature communications, vol. 11, no. 1, 562. https://doi.org/10.1038/s41467-019-14259-y

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

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.",

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

note = "Funding Information: 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. Funding Information: This work was funded by the National Research Foundation of Korea (NRF-2016R1A6A3A11933484, NRF-2017R1A2A1A17069818, and NRF-2019R1A4A1029000). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-019-14259-y",

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AU - Song, Kwon Ho

AU - Oh, Se Jin

AU - Kim, Suyeon

AU - Cho, Hanbyoul

AU - Lee, Hyo Jung

AU - Song, Joon Seon

AU - Chung, Joon Yong

AU - Cho, Eunho

AU - Lee, Jaeyoon

AU - Jeon, Seunghyun

AU - Yee, Cassian

AU - Lee, Kyung Mi

AU - Hewitt, Stephen M.

AU - Kim, Jae Hoon

AU - Woo, Seon Rang

AU - Kim, Tae Woo

N1 - Funding Information: 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. Funding Information: This work was funded by the National Research Foundation of Korea (NRF-2016R1A6A3A11933484, NRF-2017R1A2A1A17069818, and NRF-2019R1A4A1029000). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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