Ghallab Alaa M, Eissa Reda A, El Tayebi Hend M
The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Front Pharmacol. 2022 Apr 20;13:862125. doi: 10.3389/fphar.2022.862125. eCollection 2022.
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as the absence of cell surface receptors renders it more difficult to be therapeutically targeted. Chemokine receptor 2 (CXCR2) has been suggested not only to promote therapy resistance and suppress immunotherapy but it also to possess a positive cross-talk with the multifunctional cytokine transforming growth factor beta (TGF-β). Here, we showed that CXCR2 and TGF-β signaling were both upregulated in human TNBC biopsies. CXCR2 inhibition abrogated doxorubicin-mediated TGF-β upregulation in 3D TNBC coculture with PBMCs and eliminated drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC doxorubicin-resistance TGF-β signaling regulation. Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "atezolizumab" where the combined inhibition of CXCR2 and PDL1 in TNBC coculture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，由于缺乏细胞表面受体，使其更难以进行靶向治疗。趋化因子受体2（CXCR2）不仅被认为会促进治疗抗性并抑制免疫疗法，而且还与多功能细胞因子转化生长因子β（TGF-β）存在正向交互作用。在此，我们发现CXCR2和TGF-β信号通路在人TNBC活检组织中均上调。CXCR2抑制消除了在与外周血单核细胞（PBMC）共培养的三维TNBC中阿霉素介导的TGF-β上调，并消除了TNBC乳腺球中的耐药性，表明CXCR2在TNBC阿霉素耐药性TGF-β信号调节中起着至关重要的作用。此外，CXCR2抑制提高了免疫治疗药物“阿特珠单抗”的疗效，在TNBC共培养中联合抑制CXCR2和程序性死亡受体1（PDL1）在细胞毒性方面显示出累加效应。总之，当前研究表明，如果与化疗和/或免疫疗法联合使用，CXCR2抑制剂有望改善TNBC的治疗效果。
