Immune Mechanisms of Resistance to Cediranib in Ovarian Cancer

This paper 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 4-5 weeks treatment of established tumors, cediranib had anti-tumor 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 IL-6 and JAK/STAT signaling and treatment increased endothelial STAT3 activation. Combination of cediranib with a murine anti-IL-6 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 IL-6 JAK/STAT3 signaling in the TME but high PD1 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 PD1 and PDL1. Combining cediranib with an anti-PD1 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 IL-6 and PD-1 pathway expression patterns that replicated the mouse tumors. Combination of anti-IL-6 or anti-PD1 in these patients may increase activity of VEGFR inhibitors and prolong disease-free survival

The Tumor Microenvironment of Clear-Cell Ovarian Cancer

Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1A(wt)) versus ARID1A-mutant (ARID1A(mut)) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138(+) plasma cells, the LE had more CD20(+) B cells and T cells, whereas the stroma had more mast cells and αSMA(+) fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating “TGFβ remodeling of the extracellular matrix” as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1A(wt) and ARID1A(mut) CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8(+) T cells within the MCA and CD4(+) T cells at the LE and stroma significantly associated with decreased overall survival