IDDF2020-ABS-0213 CXCR2 blockade disrupts tumor trafficking of MDSC to potentiate immunotherapy efficacy

Background The heterogeneity and diverse pathogenic conditions of HCC construct an immunosuppressive tumor microenvironment (TME) which may lead to low immune checkpoint blockade (ICB) therapeutic responsiveness. Therefore, alleviating immunosuppression to potentiate ICB anti-cancer immunity is in urgent need. Myeloid-derived suppressor cells (MDSCs) with potent T cell suppressive property are correlated with poor prognosis and unsatisfactory ICB response in HCC. In this study, we aimed to study the potential efficacy and functional mechanisms of targeting C-X-C motif chemokine receptor 2 (CXCR2) chemotaxis pathway to block MDSC tumor infiltration, enhancing ICB efficacy using pre-clinical orthotopic HCC mouse models. Methods CXCR2-chemotaxis pathway activation in MDSCs was determined by multi-color flow cytometry in tumor and paired non-tumor liver specimens from HCC patients, as well as healthy blood samples. Therapeutic efficacy of CXCR2 blockade was conducted in an orthotopic mouse model using AZD5069 (100 or 150 mg/kg) which is a CXCR2 antagonist currently undergoing clinical trials and in combination with anti-PD-L1 antibody (10F.9G2). Tumorigenic monitor, immune profiling and survival analysis were performed. Mechanistic study was determined using lentivirus-based gene knockdown in human-blood cell models. Results The result showed that both monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC) populations are elevated in HCC liver tissue compared to healthy donor (HD) control. CXCR2 was widely expressed in immune cells, in particular for MDSC, while its ligand interleukin-8 (IL-8) was expressed in the majority of tumor cells, as well as CD45+ leukocytes in HCC. Notably, the blockade of CXCR2 chemotaxis pathway significantly inhibits MDSC trafficking into tumor microenvironment in HCC orthotopic mouse model. Furthermore, co-blockade of CXCR2 and PD-L1 remarkably reduced tumor weight when compared to a single treatment, in which intratumoral CXCR2+PD-L1+ MDSC was positively associated with tumor burden. Conclusions Our data demonstrated the intricate link between IL-8/CXCR2 axis and MDSC trafficking to TME, providing insight into the immunosuppression mechanism in HCC. Targeting IL-8/CXCR2 chemotaxis pathway may potentiate ICB responsiveness, serving as a novel potential therapeutic option for effectively combined immunotherapy in liver cancer.