Integrated multiomics analyses unveil the implication of a costimulatory molecule score on tumor aggressiveness and immune evasion in breast cancer: A large-scale study through over 8,000 patients

Dong Zhang; Yingnan Wang; Faming Zhao; Qifeng Yang

doi:10.1016/j.compbiomed.2023.106866

Integrated multiomics analyses unveil the implication of a costimulatory molecule score on tumor aggressiveness and immune evasion in breast cancer: A large-scale study through over 8,000 patients

Comput Biol Med. 2023 Jun:159:106866. doi: 10.1016/j.compbiomed.2023.106866. Epub 2023 Apr 5.

Authors

Dong Zhang¹, Yingnan Wang¹, Faming Zhao², Qifeng Yang³

Affiliations

¹ Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China; Department of Clinical Medicine, The First Clinical College, Shandong University, Jinan, 250012, China.
² Key Laboratory of Environmental Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
³ Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China; Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China; Research Institute of Breast Cancer, Shandong University, Jinan, 250102, China. Electronic address: qifengy_sdu@163.com.

PMID: 37068318
DOI: 10.1016/j.compbiomed.2023.106866

Abstract

Background: Although immunotherapy has revolutionised cancer management, reliable genomic biomarkers for identifying eligible patient subpopulations are lacking. Costimulatory molecules play a crucial role in mounting anti-tumour responses, and clinical trials targeting these novel biomarkers are underway. However, whether these molecules can determine tumour aggressiveness and the risk of tumour evasion in breast cancer (BC) remains largely unknown.

Methods: The whole-tissue transcriptomic data of 8236 patients with BC from 15 independent cohorts were extracted. An integrated scoring system named 'costimulatory molecule score' (CMS) was constructed and sufficient validated using least absolute shrinkage and selection operator regression (1000 iterations) and the random survival forest algorithm (1000 trees). The correlation among CMSs, cancer genotypes and clinicopathological characteristics was examined. Extensive multiomics and immunogenomic analyses were performed to investigate and verify the association among CMSs, enriched pathways, potential intrinsic and extrinsic immune escape mechanisms, immunotherapy response and therapeutic options.

Results: The predictive role of CMS model that relies on expression pattern of merely 5 costimulatory genes for prognosis is almost universally applicable to BC patients in a platform-independent manner. Through internal and external in silico validation, high CMS was characterized by favorable genotypes but decreased tumor immunogenicity, activation of stroma, immune-suppressive states and potential immunotherapeutic resistance. Similar results were observed in a real-world immunotherapy cohort and Pan-Cancer analysis.

Conclusion: This comprehensive characterization indicates CMS model may be complemented for predicting tumor aggressiveness and immune evasion in BC patients, underlining the future clinical potential for further exploration of resistance mechanisms and optimization of immunotherapeutic strategies.

Keywords: Breast cancer; Costimulatory molecule; Immune evasion; Immunotherapeutic response; Multiomics analysis; Tumour microenvironment.

Publication types

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

MeSH terms

Animals
Breast Neoplasms* / genetics
Female
Gene Expression Profiling
Humans
Immune Evasion
Mammary Neoplasms, Animal*
Multiomics