CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer

Abstract

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 in vitro TNBC coculture with PBMCs and eliminated drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC doxorubicin-resistance via 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 in vitro 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.

Neutrophils in the era of single-cell RNA sequencing: functions and targeted therapies in cancer

“…Targeting neutrophils is challenging owing to the lack of tractable targets; however, inhibition of C–X–C chemokine receptor 2 (CXCR2) and its ligand, C–X–C chemokine ligand 8 (CXCL8, also known as IL-8), has been used to prevent neutrophil recruitment to tissues 17 . A recent study suggested that the CXCR2 inhibitor, AZD5069, is a promising approach to improve triple-negative breast cancer treatment because the blockade of CXCR2 significantly reduces the infiltration of neutrophils and improves the efficacy of immune checkpoint blockade in in vitro tests 18 . Tumor cells also induce neutrophil extrusion of NETs by secreting CXCR2 ligands 4 .…”

Multifaceted Roles of Chemokine C-X-C Motif Ligand 7 in Inflammatory Diseases and Cancer

“…However, it was not associated with the improved clinical outcomes explored in the trial, so additional clinical trials are needed to explore its effectiveness ( O'Byrne et al, 2016 ; De Soyza et al, 2015 ). AZD5069 has been shown to improve TGF-β signaling pathway-mediated adriamycin resistance through inhibition of CXCR2 in triple-negative breast cancer cells and to enhance atezolizumab immunotherapy efficacy ( Ghallab et al, 2022 ). Therefore, the results of the ongoing clinical trials of AZD5069 antitumor therapy are worthy of our expectation.…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…They can also polarize neutrophils to a pro-tumorigenic phenotype [ 26 , 226 ]. CXCR2 upregulation was found in TNBC themselves and was suggested as a novel cancer stem-like cell marker for TNBC [ 272 , 273 ]. Ghallab et al showed that CXCR2 inhibition with the small-molecule inhibitor AZD5069 in TNBC culture eliminated doxorubicin resistance and improved the efficacy of atezolizumab, a monoclonal antibody against PD-L1 [ 273 ].…”

“…CXCR2 upregulation was found in TNBC themselves and was suggested as a novel cancer stem-like cell marker for TNBC [ 272 , 273 ]. Ghallab et al showed that CXCR2 inhibition with the small-molecule inhibitor AZD5069 in TNBC culture eliminated doxorubicin resistance and improved the efficacy of atezolizumab, a monoclonal antibody against PD-L1 [ 273 ]. In the HCC with non-alcoholic steatohepatitis (NASH-HCC) mouse model resistant to anti-PD-1, AZD5069/anti-PD-1 combination therapy suppressed the tumor burden and extended survival [ 274 ].…”