Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/ijms22020535
Keywords
chemoradiotherapy; cisplatin; immunotherapy; carcinoma; transitional cell; immunogenic cell death
Funding
- Suzuki Urological Foundation
- JSPS KAKENHI [19K18553]
- Grants-in-Aid for Scientific Research [19K18553] Funding Source: KAKEN
Ask authors/readers for more resources
The combination of cisplatin and irradiation, known as chemoradiotherapy (CRT), has been shown to enhance the efficacy of postirradiation anti-programmed cell death 1 (PD-1) treatment in urothelial carcinoma (UC) patients. In mouse models, CRT combined with postirradiation anti-PD-1 treatment resulted in significantly slower tumor growth, higher expression of cytotoxic T cells, and improved survival compared to anti-PD-1 treatment alone, indicating the potential of CRT in enhancing antitumor immunity. Mechanistically, CRT induces immunogenic cell death and potentiates the effectiveness of postirradiation anti-PD-1 treatment in UC.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available