Ischemia and reperfusion injury combined with cisplatin induces immunogenic cell death in lung cancer cells

Shuai Zhang; Yumei Li; Shuqing Liu; Pei Ma; Mengfei Guo; E Zhou; Limin Duan; Jinshuo Fan; Tingting Liao; Qi Tan; Xuan Wang; Feng Wu; Yang Jin

doi:10.1038/s41419-022-05176-y

Ischemia and reperfusion injury combined with cisplatin induces immunogenic cell death in lung cancer cells

Cell Death Dis. 2022 Sep 3;13(9):764. doi: 10.1038/s41419-022-05176-y.

Authors

Shuai Zhang^#¹, Yumei Li^#¹, Shuqing Liu^#^{1

2}, Pei Ma^{1

3}, Mengfei Guo¹, E Zhou¹, Limin Duan^{1

4}, Jinshuo Fan¹, Tingting Liao¹, Qi Tan¹, Xuan Wang¹, Feng Wu⁵, Yang Jin⁶

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Diseases of National Health Commission, Clinical Research Center for major respiratory diseases in Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
² Department of Respiratory and Critical Care Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
³ State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁵ Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Diseases of National Health Commission, Clinical Research Center for major respiratory diseases in Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. wufengxiehe@163.com.
⁶ Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Diseases of National Health Commission, Clinical Research Center for major respiratory diseases in Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. whuhjy@126.com.

^# Contributed equally.

Abstract

A first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), cisplatin (CDDP), fails to induce immunogenic cell death (ICD) because it fails to induce calreticulin (CRT) exposure on the cell surface. We investigated the potential of ischemia and reperfusion injury (I/R) combined with CDDP to induce ICD in lung cancer cells. The in vitro model of I/R, oxygen-glucose deprivation and reperfusion (OGD/R), effectively induced CRT exposure, ATP secretion, high mobility group box 1 (HMGB1) release and eIF2α phosphorylation in both Lewis lung carcinoma (LLC) and A549 cells when combined with CDDP. By using a vaccine assay and coculture with bone marrow-derived dendritic cells (BMDCs), we showed that OGD/R restored the immunogenicity of CDDP by phosphorylating eIF2α and demonstrated that OGD/R + CDDP (O + C) is an ICD inducer. Using the inguinal tumor model, we found that I/R significantly enhanced the tumor-killing effect of CDDP and Mitomycin C, and this effect relied on adaptive antitumor immunity. Consistently, I + C altered the ratio of interferon-gamma-secreting T lymphocytes, thus overcoming the immunosuppressive effect induced by CDDP. In conclusion, our research presents a new combination strategy and indicates that I/R is a potential anticancer immunogenic modality when combined with nonimmunogenic chemotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis
Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Cisplatin / pharmacology
Cisplatin / therapeutic use
Humans
Immunogenic Cell Death
Ischemia / drug therapy
Lung Neoplasms* / drug therapy
Reperfusion Injury* / drug therapy

Substances

Antineoplastic Agents
Cisplatin