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Published on: June 12, 2021
CXCL10 potentiates immune checkpoint blockade therapy in homologous recombination-deficient tumors
Zhiwen Shi1,2, Jianfeng Shen3,4, Junjun Qiu1,2
1Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regualtion, Shanghai Institute of Planned Parenthood Research, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200032, China.
Abstract:
Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability, and has been proven to be a biomarker for target therapy. However, until now, no research has explored the changes in the transcriptomics landscape of HRD tumors. Methods: The HRD score was established from SNP array data of breast cancer patients from the cancer genome atlas (TCGA) database. The transcriptome data of patients with different HRD scores were analyzed to identify biomarkers associated with HRD. The candidate biomarkers were validated in the gene expression omnibus (GEO) database and immunotherapy cohorts. Results: Based on data from the gene expression profile and clinical characteristics from 1310 breast cancer patients, including TCGA database and GEO database, we found that downstream targets of the cGAS-STING pathway, such as CXCL10, were upregulated in HRD tumors and could be used as a predictor of survival outcome in triple-negative breast cancer (TNBC) patients. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that the expression of CXCL10 was positively correlated with neoantigen load and infiltrating immune cells. Finally, in vivo experimental data and clinical trial data confirmed that the expression of CXCL10 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Conclusions: Together, our study not only revealed that CXCL10 is associated with HRD but also introduced a potential new perspective for identifying prognostic biomarkers of immunotherapy.
Insights
Homologous recombination deficiency (HRD) in breast cancer is linked to increased CXCL10 expression. This finding suggests CXCL10 may predict survival and response to immunotherapy, particularly in triple-negative breast cancer.
Area of Science:
- Genomics
- Cancer Biology
- Immunology
Background:
- Homologous recombination deficiency (HRD) is a key feature of genomic instability and a biomarker for targeted therapies.
- The transcriptomic landscape of HRD tumors remains largely unexplored.
- Understanding HRD-associated molecular changes is crucial for advancing cancer treatment strategies.
Purpose of the Study:
- To investigate the transcriptomic alterations in tumors with homologous recombination deficiency (HRD).
- To identify novel biomarkers associated with HRD and predict patient outcomes.
- To explore the potential of identified biomarkers in predicting response to cancer immunotherapies.
Main Methods:
- Calculated HRD scores using SNP array data from The Cancer Genome Atlas (TCGA) breast cancer cohort.
- Analyzed transcriptome data to identify HRD-associated gene expression changes.
- Validated candidate biomarkers in the Gene Expression Omnibus (GEO) database and immunotherapy cohorts.
Main Results:
- Downstream targets of the cGAS-STING pathway, including CXCL10, were upregulated in HRD tumors.
- CXCL10 expression served as a predictor of survival outcomes in triple-negative breast cancer (TNBC).
- CXCL10 expression correlated positively with neoantigen load and immune cell infiltration in the tumor immune microenvironment.
- CXCL10 expression was confirmed as a biomarker for anti-PD-1/PD-L1 therapy response.
Conclusions:
- CXCL10 is significantly associated with homologous recombination deficiency (HRD) in breast cancer.
- CXCL10 emerges as a potential prognostic biomarker for immunotherapy.
- This study offers a new perspective for identifying biomarkers to guide immunotherapy selection.
