Myeloid cell-derived interleukin 1b promotes chemoresistance in metastatic ovarian cancer

Most ovarian cancer (OC) patients respond to the front-line chemotherapy but succumb to chemoresistant relapse with peritoneal metastases. How chemoresistance develops in OC patients after the front-line chemotherapy remains poorly understood. Recent understanding of the tumor immune microenvironment (TIME) suggests that inflammatory mediators from myeloid cells play key roles in developing chemoresistance. This proposal seeks to understand whether and how a classical inflammatory mediator from myeloid cells, interleukin 1β (IL1β), promotes OC chemoresistance, aiming to eradicate metastatic OC by overcoming IL1β-mediated chemoresistance. Based on published and our preliminary results, we hypothesize that myeloid cell-derived IL1β promotes chemoresistance in metastatic OC by modifying TIME via activation of OC cells and fibroblasts; combining IL1β neutralization and chemotherapy eliminates chemoresistant OC. This will be tested with the following Aims. Aim 1: Test the hypothesis that the combination of chemotherapy and IL1β neutralization overcomes OC chemoresistance. Aim 2: Test the hypothesis that myeloid cell-derived IL1β drives OC chemoresistance by modifying TIME. Aim 3: Test the hypothesis that myeloid-derived IL1β promotes formation of chemoresistant spheroids. Project Number: 1R21CA297425-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Nan Zhang | Institution: WISTAR INSTITUTE, PHILADELPHIA, PA | Award Amount: $473,624 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-X (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11281912