Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma

Minsu Kwon; Gi Hoon Nam; Hanul Jung; Seong A. Kim; Seohyun Kim; Yeonju Choi; Yoon Se Lee; Hyo Jung Cho; In San Kim

doi:10.1016/j.canlet.2021.09.029

Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma

Minsu Kwon, Gi Hoon Nam, Hanul Jung, Seong A. Kim, Seohyun Kim, Yeonju Choi, Yoon Se Lee, Hyo Jung Cho, In San Kim

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

24 Citations (Scopus)

Abstract

The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8⁺ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.

Original language	English
Pages (from-to)	198-210
Number of pages	13
Journal	Cancer letters
Volume	522
DOIs	https://doi.org/10.1016/j.canlet.2021.09.029
Publication status	Published - 2021 Dec 1

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( 2017R1A3B1023418 from I–S. Kim and 2020R1C1C1003539 from M. Kwon) in Korea.

Publisher Copyright:
© 2021

Keywords

Anticancer drug combinations
Cis-diamminedichloroplatinum (II)
Head and neck neoplasms
Hydroxymethylglutaryl-CoA reductase inhibitors
Immunogenic cell death

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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

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10.1016/j.canlet.2021.09.029

Cite this

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title = "Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma",

abstract = "The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.",

keywords = "Anticancer drug combinations, Cis-diamminedichloroplatinum (II), Head and neck neoplasms, Hydroxymethylglutaryl-CoA reductase inhibitors, Immunogenic cell death",

author = "Minsu Kwon and Nam, {Gi Hoon} and Hanul Jung and Kim, {Seong A.} and Seohyun Kim and Yeonju Choi and Lee, {Yoon Se} and Cho, {Hyo Jung} and Kim, {In San}",

note = "Funding Information: This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( 2017R1A3B1023418 from I–S. Kim and 2020R1C1C1003539 from M. Kwon) in Korea. Publisher Copyright: {\textcopyright} 2021",

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T1 - Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma

AU - Kwon, Minsu

AU - Nam, Gi Hoon

AU - Jung, Hanul

AU - Kim, Seong A.

AU - Kim, Seohyun

AU - Choi, Yeonju

AU - Lee, Yoon Se

AU - Cho, Hyo Jung

AU - Kim, In San

N1 - Funding Information: This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT ( 2017R1A3B1023418 from I–S. Kim and 2020R1C1C1003539 from M. Kwon) in Korea. Publisher Copyright: © 2021

PY - 2021/12/1

Y1 - 2021/12/1

N2 - The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.

AB - The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.

KW - Anticancer drug combinations

KW - Cis-diamminedichloroplatinum (II)

KW - Head and neck neoplasms

KW - Hydroxymethylglutaryl-CoA reductase inhibitors

KW - Immunogenic cell death

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SN - 0304-3835

VL - 522

SP - 198

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JO - Cancer letters

JF - Cancer letters

ER -

Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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