An immunosuppressive subtype of senescent tumor cells predicted worse immunotherapy response in lung adenocarcinoma

Guangyu Fan; Tongji Xie; Qiaoyun Tan; Ning Lou; Shasha Wang; Xiaohong Han; Yuankai Shi

doi:10.1016/j.isci.2023.107894

An immunosuppressive subtype of senescent tumor cells predicted worse immunotherapy response in lung adenocarcinoma

iScience. 2023 Sep 9;26(10):107894. doi: 10.1016/j.isci.2023.107894. eCollection 2023 Oct 20.

Authors

Guangyu Fan¹, Tongji Xie¹, Qiaoyun Tan², Ning Lou³, Shasha Wang³, Xiaohong Han⁴, Yuankai Shi¹

Affiliations

¹ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
² Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, N0.109，Machang Road, Jianghan District, Wuhan 430024, China.
³ Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
⁴ Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing 100730, China.

Abstract

Senescent tumor cells (STCs) can induce immunosuppression, promoting tumor progression and therapy resistance. However, the specific characteristics of immunosuppressive STC have not been thoroughly investigated. This study aimed to characterize and elucidate the immunosuppressive phenotype of STC in lung adenocarcinoma by employing single-cell and bulk transcriptomics, as well as serum proteomics profiling. We identified senescence-related genes specific to tumors and identified Cluster10 of STC as the immunomodulatory subtype. Cluster10 exhibited a distinct secretome dominated by cytokines such as CXCL1, CXCL2, and CXCL8 and showed activation of transcription factors associated with cytokine secretion, including NFKB1, RELA, and STAT3. Notably, Cluster10 demonstrated the highest degree of intercellular communication among all cell types, with interactions as LGALS9-TIM3 and MIF-CD74. Furthermore, Cluster10 showed significant associations with poor prognosis and diminished response to immunotherapy. Analysis of serum proteomics data from our in-house cohort identified CXCL8 as a potential marker for predicting immunotherapeutic outcomes.

Keywords: Bioinformatics; Cancer; Components of the immune system; Immunology; Proteomics; Transcriptomics.