Inhibiting CXCR2 Remodels the Tumor Microenvironment and Blunts Tumor Progression and Dissemination of High-Grade Serous Carcinoma

Abstract

Abstract High-grade serous carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum has an immunosuppressive tumor immune microenvironment (TIME), mediated in part by infiltrating innate immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells (MDSC). We hypothesize that manipulating these immunoinhibitory cells will improve both response to treatment and outcomes for patients with HGSC. Using publicly available databases, we demonstrate that higher expression of CXCR2, a chemotactic receptor for MDSCs and neutrophils, is correlated with decreased overall survival and increased infiltration of neutrophils, monocytes, and M2-like macrophages in HGSC. We targeted the migration of MDSCs and neutrophils to the TIME in the ID8-p53null mouse model of HGSC with the CXCR2-selective inhibitor SB-225002 (CXCR2i) alone or in combination with cisplatin. Tumor weight and dissemination were decreased in mice treated with single-agent cisplatin or CXCR2i. In cisplatin-treated tumors compared with vehicle-treated tumors, there was an increase in suppressive myeloid cells measured by flow cytometry and multispectral immunohistochemistry. Moreover, cisplatin-mediated modulation of tumor immune cell populations was abrogated by the addition of CXCR2i to cisplatin treatment. These findings demonstrate that inhibition of CXCR2 can slow tumor progression and decrease the proportion of immunosuppressive myeloid immune cells in the TIME. Furthermore, these data reveal new insights into detrimental chemotherapy-induced remodeling of the TIME, which should be investigated as mechanistic targets to improve outcomes in HGSC. Overall, our data demonstrate the clinical relevance and therapeutic potential of targeting CXCR2 to prevent the recruitment of tumor-promoting innate immune cells to the TIME. Significance: Chemotherapy is effective in HGSC but rarely leads to a cure. We demonstrate that chemotherapy induces active CD8+ T cells with a concomitant increase in immunosuppressive myeloid cells in the tumor microenvironment. The chemotherapy-induced migration of immunosuppressive myeloid cells is inhibited by a CXCR2i without affecting the activated T cells. We purport that inhibiting CXCR2 with chemotherapy in HGSC will improve T-cell immune surveillance in HGSC and patient outcomes.