A. Ghallab (New Cairo, Egypt)
Author Of 1 Presentation
88P - CXCR2 Small Molecule Antagonists: a Novel Approach to Enhance the Effect of PDL-1 Inhibitors in Triple Negative Breast Cancer
Abstract
Background
Immunologic checkpoint blockade (ICB) is a novel approach to reverse cancer immunosuppression. Various studies observed the role of CXCR2 in tumour aggressiveness, resistance and immune-suppression. CXCR2 signaling is known to recruit myeloid derived suppressor cells (MDSCs) to tumor microenvironment where MDSCs oppose the cytotoxic T-cell-mediated antitumor effect and suppress ICB efficacy. CXCR2 inhibition was found to augment programed cell death-1 (PD-1) inhibition in pancreatic cancer. CXCR2 inhibition has been proposed as an attractive anti-tumor treatment not only to enhance immunotherapy, but also to intensify the cytotoxicity of chemotherapeutic drugs. We have previously reported the enhaced chemosensitivty of TNBC mammospheres to Doxorubicin by AZD5069 \"a selective small-molecule antagonist of human CXCR2”. Here, we investigate the potential use of AZD5069 in combination with atezolizumab (anti-PD-L1) in an ex-vivo TNBC model.
Methods
CXCR2 mRNA expression was analyzed using RealTime PCR in 65 BC biopsies and controls. MDA-MB231 cells was co-cultured with PBMCs isolated from TNBC patients’ blood (Ficoll protocol). Lactate dehrdrogenase-LDH cytotoxicity assay was performed on the ex-vivo model treated with 200 nm anti-PD-L1 and/or (10, 30, 100nm) AZD5069 for 72 hours.
Results
The relative expression of CXCR2 was found to be markedly increased in BC patients. TNBC and HER2 +ve patients showed a dramatic elevation in CXCR2 expression (p=0.0039,p=0.0286, respectively), hormonal subtypes (ER, PR +/- and HER2–ve) showed mild overexpression of CXCR2 (p=0.0179) compared to controls. While CXCR2 expression was significantly higher in TNBC patients compared to other subtypes (p=0.0199). In LDH assay, combination of 30 nm AZD5069(inhibitory dose for PBMCs according to dose-response curve) and 200 nm anti-PD-L1 induced a significant additive effect in cytotoxicity than anti-PD-L1 alone (p=0.0065). While the non-effective doses of AZD5069(10,100 nm) in combination with anti-PD-L1 showed no significant effect (P=0.073, P=0.182, respectively).
Conclusions
These data highlight the role of CXCR2 inhibition as a cutting edge approach to boost immunotherapy and combat chemo-resistance in TNBC.
Legal entity responsible for the study
German University in Cairo - GUC.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Presenter Of 1 Presentation
88P - CXCR2 Small Molecule Antagonists: a Novel Approach to Enhance the Effect of PDL-1 Inhibitors in Triple Negative Breast Cancer
Abstract
Background
Immunologic checkpoint blockade (ICB) is a novel approach to reverse cancer immunosuppression. Various studies observed the role of CXCR2 in tumour aggressiveness, resistance and immune-suppression. CXCR2 signaling is known to recruit myeloid derived suppressor cells (MDSCs) to tumor microenvironment where MDSCs oppose the cytotoxic T-cell-mediated antitumor effect and suppress ICB efficacy. CXCR2 inhibition was found to augment programed cell death-1 (PD-1) inhibition in pancreatic cancer. CXCR2 inhibition has been proposed as an attractive anti-tumor treatment not only to enhance immunotherapy, but also to intensify the cytotoxicity of chemotherapeutic drugs. We have previously reported the enhaced chemosensitivty of TNBC mammospheres to Doxorubicin by AZD5069 \"a selective small-molecule antagonist of human CXCR2”. Here, we investigate the potential use of AZD5069 in combination with atezolizumab (anti-PD-L1) in an ex-vivo TNBC model.
Methods
CXCR2 mRNA expression was analyzed using RealTime PCR in 65 BC biopsies and controls. MDA-MB231 cells was co-cultured with PBMCs isolated from TNBC patients’ blood (Ficoll protocol). Lactate dehrdrogenase-LDH cytotoxicity assay was performed on the ex-vivo model treated with 200 nm anti-PD-L1 and/or (10, 30, 100nm) AZD5069 for 72 hours.
Results
The relative expression of CXCR2 was found to be markedly increased in BC patients. TNBC and HER2 +ve patients showed a dramatic elevation in CXCR2 expression (p=0.0039,p=0.0286, respectively), hormonal subtypes (ER, PR +/- and HER2–ve) showed mild overexpression of CXCR2 (p=0.0179) compared to controls. While CXCR2 expression was significantly higher in TNBC patients compared to other subtypes (p=0.0199). In LDH assay, combination of 30 nm AZD5069(inhibitory dose for PBMCs according to dose-response curve) and 200 nm anti-PD-L1 induced a significant additive effect in cytotoxicity than anti-PD-L1 alone (p=0.0065). While the non-effective doses of AZD5069(10,100 nm) in combination with anti-PD-L1 showed no significant effect (P=0.073, P=0.182, respectively).
Conclusions
These data highlight the role of CXCR2 inhibition as a cutting edge approach to boost immunotherapy and combat chemo-resistance in TNBC.
Legal entity responsible for the study
German University in Cairo - GUC.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.