The immune checkpoint adenosine 2A receptor is associated with aggressive clinical outcomes and reflects an immunosuppressive tumor microenvironment in human breast cancer

Frontiers in Immunology

Immunology

Ibtissam Razzouki¹  Mehdi Karkouri¹  Hamza Benthami²  Ibtissam Rezouki²  Basma Zohair²  Abdallah Badou³  Mohamed Elkarroumi⁴  Dounia Chraa⁵  Daniel Olive⁵ 

[1] Department of Pathological Anatomy, Ibn Rochd University Hospital Center, Casablanca, Morocco;Immuno-Genetics and Human Pathology Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco;Immuno-Genetics and Human Pathology Laboratory (LIGEP), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco;Mohammed VI Center for Research & Innovation, Rabat, Morocco and Mohammed VI University of Sciences and Health, Casablanca, Morocco;Mohamed VI Oncology Center, Ibn Rochd University Hospital Center, Casablanca, Morocco;Team Immunity and Cancer, The Cancer Research Center of Marseille (CRCM), Inserm, 41068, CNRS, UMR7258, Paoli-Calmettes Institute, Aix-Marseille University, UM 105, Marseille, France;

关键词: A2AR;    PD-1;    CTLA-4;    tumor and immune microenvironment;    immunosuppression;    immune checkpoint;    immunotherapy;    breast cancer prognosis;   

DOI  :  10.3389/fimmu.2023.1201632

 received in 2023-04-06, accepted in 2023-08-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe crosstalk between the immune system and cancer cells has aroused considerable interest over the past decades. To escape immune surveillance cancer cells evolve various strategies orchestrating tumor microenvironment. The discovery of the inhibitory immune checkpoints was a major breakthrough due to their crucial contribution to immune evasion. The A2AR receptor represents one of the most essential pathways within the TME. It is involved in several processes such as hypoxia, tumor progression, and chemoresistance. However, its clinical and immunological significance in human breast cancer remains elusive.MethodsThe mRNA expression and protein analysis were performed by RT-qPCR and immunohistochemistry. The log-rank (Mantel-Cox) test was used to estimate Kaplan-Meier analysis for overall survival. Using large-scale microarray data (METABRIC), digital cytometry was conducted to estimate cell abundance. Analysis was performed using RStudio software (7.8 + 2023.03.0) with EPIC, CIBERSORT, and ImmuneCellAI algorithms. Tumor purity, stromal and immune scores were calculated using the ESTIMATE computational method. Finally, analysis of gene set enrichment (GSEA) and the TISCH2 scRNA-seq database were carried out.ResultsGene and protein analysis showed that A2AR was overexpressed in breast tumors and was significantly associated with high grade, elevated Ki-67, aggressive molecular and histological subtypes, as well as poor survival. On tumor infiltrating immune cells, A2AR was found to correlate positively with PD-1 and negatively with CTLA-4. On the other hand, our findings disclosed more profuse infiltration of protumoral cells such as M0 and M2 macrophages, Tregs, endothelial and exhausted CD8+ T cells within A2ARhigh tumors. According to the Single-Cell database, A2AR is expressed in malignant, stromal and immune cells. Moreover, it is related to tumor purity, stromal and immune scores. Our results also revealed that CD8+T cells from A2ARhigh patients exhibited an exhausted functional profile. Finally, GSEA analysis highlighted the association of A2AR with biological mechanisms involved in tumor escape and progression.ConclusionThe present study is the first to elucidate the clinical and immunological relevance of A2AR in breast cancer patients. In light of these findings, A2AR could be deemed a promising therapeutic target to overcome immune evasion prevailing within the TME of breast cancer patients.

【 授权许可】

Unknown   
Copyright © 2023 Zohair, Chraa, Rezouki, Benthami, Razzouki, Elkarroumi, Olive, Karkouri and Badou