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

• Published in: International journal of molecular sciences Vol. 22; no. 2; p. 535
• Main Authors: Fukushima, Hiroshi, Yoshida, Soichiro, Kijima, Toshiki, Nakamura, Yuki, Fukuda, Shohei, Uehara, Sho, Yasuda, Yosuke, Tanaka, Hajime, Yokoyama, Minato, Matsuoka, Yoh, Fujii, Yasuhisa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.01.2021; MDPI
• Subjects: Animal models; Animals; Antibodies; Antineoplastic Agents, Immunological - pharmacology; Apoptosis; Bladder cancer; carcinoma; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - pathology; Carcinoma - radiotherapy; Cell culture; Cell death; Chemoradiotherapy; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Combined Modality Therapy; Cytotoxicity; Growth rate; Heterografts; Humans; Immune checkpoint inhibitors; immunogenic cell death; Immunogenic Cell Death - drug effects; Immunogenicity; immunotherapy; Investigations; Irradiation; Lymphocytes; Lymphocytes T; Medical prognosis; Metastasis; Mice; Monoclonal antibodies; PD-1 protein; Pembrolizumab; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Radiation; Radiation therapy; Survival; Targeted cancer therapy; transitional cell; Tumors; Urothelial carcinoma; Urothelium - drug effects; Urothelium - pathology; Urothelium - radiation effects; chemoradiotherapy; cisplatin; carcinoma; immunogenic cell death; immunotherapy; transitional cell
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22020535

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.