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Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma

The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiati...

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Autores principales: Fukushima, Hiroshi, Yoshida, Soichiro, Kijima, Toshiki, Nakamura, Yuki, Fukuda, Shohei, Uehara, Sho, Yasuda, Yosuke, Tanaka, Hajime, Yokoyama, Minato, Matsuoka, Yoh, Fujii, Yasuhisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825793/
https://www.ncbi.nlm.nih.gov/pubmed/33430352
http://dx.doi.org/10.3390/ijms22020535
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author Fukushima, Hiroshi
Yoshida, Soichiro
Kijima, Toshiki
Nakamura, Yuki
Fukuda, Shohei
Uehara, Sho
Yasuda, Yosuke
Tanaka, Hajime
Yokoyama, Minato
Matsuoka, Yoh
Fujii, Yasuhisa
author_facet Fukushima, Hiroshi
Yoshida, Soichiro
Kijima, Toshiki
Nakamura, Yuki
Fukuda, Shohei
Uehara, Sho
Yasuda, Yosuke
Tanaka, Hajime
Yokoyama, Minato
Matsuoka, Yoh
Fujii, Yasuhisa
author_sort Fukushima, Hiroshi
collection PubMed
description The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti–programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti–PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti–PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti–PD-1 treatment alone. The mice treated with CRT/postirradiation anti–PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti–PD-1 treatment efficacy in UC.
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spelling pubmed-78257932021-01-24 Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma Fukushima, Hiroshi Yoshida, Soichiro Kijima, Toshiki Nakamura, Yuki Fukuda, Shohei Uehara, Sho Yasuda, Yosuke Tanaka, Hajime Yokoyama, Minato Matsuoka, Yoh Fujii, Yasuhisa Int J Mol Sci Article The therapeutic benefit of immune checkpoint inhibitor monotherapy is limited to a subset of patients in urothelial carcinoma (UC). Previous studies showed the immunogenicity of cisplatin and irradiation. Here, we investigated whether chemoradiotherapy (CRT), a combination of cisplatin and irradiation, could improve the efficacy of postirradiation anti–programmed cell death 1 (PD-1) treatment in UC. In our advanced UC patient cohort, patients with CRT showed a significantly better objective response rate (75%/22%) and overall survival (88%/30% at 12 months) following later pembrolizumab therapy compared to those without. Then, we created syngeneic UC mouse models by inoculating MB49 cells s.c. in C57BL/6J mice to examine the potential of CRT to enhance antitumor immunity in conjunction with postirradiation anti–PD-1 treatment. Nonirradiated tumors of the mice treated with CRT/postirradiation anti–PD-1 treatment had a significantly slower growth rate and a significantly higher expression of cytotoxic T cells compared to those of the mice treated with anti–PD-1 treatment alone. The mice treated with CRT/postirradiation anti–PD-1 treatment showed the best survival. Mechanistically, CRT provoked strong direct cytotoxicity and increased expressions of immunogenic cell death markers in MB49 cells. Therefore, the combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti–PD-1 treatment efficacy in UC. MDPI 2021-01-07 /pmc/articles/PMC7825793/ /pubmed/33430352 http://dx.doi.org/10.3390/ijms22020535 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fukushima, Hiroshi
Yoshida, Soichiro
Kijima, Toshiki
Nakamura, Yuki
Fukuda, Shohei
Uehara, Sho
Yasuda, Yosuke
Tanaka, Hajime
Yokoyama, Minato
Matsuoka, Yoh
Fujii, Yasuhisa
Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title_full Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title_fullStr Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title_full_unstemmed Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title_short Combination of Cisplatin and Irradiation Induces Immunogenic Cell Death and Potentiates Postirradiation Anti–PD-1 Treatment Efficacy in Urothelial Carcinoma
title_sort combination of cisplatin and irradiation induces immunogenic cell death and potentiates postirradiation anti–pd-1 treatment efficacy in urothelial carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825793/
https://www.ncbi.nlm.nih.gov/pubmed/33430352
http://dx.doi.org/10.3390/ijms22020535
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