The Influence of Macrophages within the Tumor Microenvironment on Ovarian Cancer Growth and Response to Therapies

Abstract

While the majority of ovarian cancer (OC) patients respond to front-line carboplatin/paclitaxel chemotherapy and surgical debulking, nearly all patients will develop platinum-resistance and recur. Our study investigates how tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) affect chemotherapy outcomes using OC patient-derived organoids and humanized patient-derived xenografts (huPDX). In vitro macrophage migration assays demonstrate the selective recruitment of M2 polarized macrophages to OC organoids. M2 macrophages, but not M1 macrophages, increase OC organoid viability and reduce their sensitivity to paclitaxel in co-culture assays. Furthermore, we identified BMS777607, a receptor tyrosine kinase inhibitor, that is capable of repolarizing M2 macrophages in vitro and reduces organoid viability by a macrophage-dependent mechanism. In a platinum-sensitive humanized patient-derived xenograft (huPDX) model, the presence of human immune cells increased between-mouse variability in response to paclitaxel with two of four mice demonstrating tumor regrowth after two weeks of treatment. A TAM-targeted CSF-1R inhibitor, BLZ945 significantly reduced the total number of human immune cells within the ascites fluid of huPDX3 mice, but did not reduce tumor burden. However BLZ945 in combination with paclitaxel reduced tumor burden with no sign of regrowth. Our study demonstrates that patient-derived OC organoids and huPDX, are useful for evaluating the immunomodulatory effects of therapies and the influence of TAMs on response. huPDX models could serve as a robust platform for preclinical testing of novel anti-cancer treatments, providing insights into the complex interplay between immune cells and cancer therapeutics.