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Supplementary Figure from Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

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posted on 2023-04-03, 18:48 authored by Ganga Gopinathan, Chiara Berlato, Anissa Lakhani, Ludmila Szabova, Colin Pegrum, Ana-Rita Pedrosa, Florian Laforets, Eleni Maniati, Frances R. Balkwill
Supplementary Figure from Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

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Cancer Research UK

Cancer Research UK City of London Centre

Cancer Research UK

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Cancer Research UK Centre of Excellence Award

Barts Cancer Institute

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ARTICLE ABSTRACT

This article investigates mechanisms of resistance to the VEGF receptor inhibitor cediranib in high-grade serous ovarian cancer (HGSOC), and defines rational combination therapies. We used three different syngeneic orthotopic mouse HGSOC models that replicated the human tumor microenvironment (TME). After 4 to 5 weeks treatment of established tumors, cediranib had antitumor activity with increased tumor T-cell infiltrates and alterations in myeloid cells. However, continued cediranib treatment did not change overall survival or the immune microenvironment in two of the three models. Moreover, treated mice developed additional peritoneal metastases not seen in controls. Cediranib-resistant tumors had intrinsically high levels of IL6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. 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. 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. 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. Combining cediranib with an anti–PD-1 antibody was superior to monotherapy in this model, increasing T cells and decreasing blood vessel densities. 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. Combination of anti-IL6 or anti–PD-1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival.

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    Molecular Cancer Therapeutics

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