We have previously investigated the role of IL6 in regulating the inflammatory cytokine network found in HGSOC ( 6, 7) and in a series of ex vivo and human tumor xenograft experiments, found that this cytokine directly stimulated angiogenesis with defective pericyte coverage ( 8). Combination of anti-IL6 or anti–PD-1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival. Bioinformatics analysis of two human HGSOC transcriptional datasets revealed distinct clusters of tumors with IL6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combining cediranib with an anti–PD-1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. When the mice eventually relapsed, pSTAT3 was still reduced in the tumors but there were high levels of immune cell PD-1 and Programmed death-ligand 1. In a third HGSOC model, that had lower inherent IL6 JAK/STAT3 signaling in the TME but high programmed cell death protein 1 (PD-1) signaling, long-term cediranib treatment significantly increased overall survival. Combination of cediranib with a murine anti-IL6 antibody was superior to monotherapy, increasing mouse survival, reducing blood vessel density, and pSTAT3, with increased T-cell infiltrates in both models. Cediranib-resistant tumors had intrinsically high levels of IL6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Moreover, treated mice developed additional peritoneal metastases not seen in controls. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. After 4 to 5 weeks treatment of established tumors, cediranib had antitumor activity with increased tumor T-cell infiltrates and alterations in myeloid cells. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment (TME). This article investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer (HGSOC), and defines rational combination therapies.
0 kommentar(er)
