Longitudinal Modulation of Loco-Regional Immunity in Ovarian Cancer Patients Receiving Intraperitoneal Chemotherapy

Abstract

The immune tumor microenvironment (TME) of epithelial ovarian cancer (EOC) carries both effector and suppressive functions. To define immune correlates of chemotherapy-induced tumor involution, we performed longitudinal evaluation of biomarker expression on serial biological specimens collected during intraperitoneal (IP) platinum-based chemotherapy. Serial biological samples were collected at several time points during IP chemotherapy. RNA from IP fluid cells and tumor tissue was analyzed via NanoString. Meso Scale Discovery (MSD) multiplex assay and ELISA for MUC1 antibodies were performed on plasma and IP fluid. Differentially expressed genes in IP fluid demonstrate an upregulation of B cell function and activation of Th2 immune response along with dampening of Th1 immunity during chemotherapy. MSD analysis of IP fluid and gene expression analysis of tumor tissue revealed activation of Th2 immunity and the complement system. Anti-MUC1 antibodies were detected in IP fluid samples. IP fluid analysis in a secondary cohort also identified chemotherapy-induced B cell function genes. This study shows that serial IP fluid sampling is an effective method to capture changes in the immune TME during chemotherapy and reveals treatment induced changes in B cell function and Th2 immunity.

Breaking Barriers: Modulation of Tumor Microenvironment to Enhance Bacillus Calmette–Guérin Immunotherapy of Bladder Cancer

“…Since the balance between CTLs and suppressive cells within the TME is a strong prognostic factor for bladder cancer outcomes, correcting it is likely to correct the limitations of BCG therapies, prolonging their duration and possibly extending their efficacy to MIBC when used alone or as a part of combinatorial treatments involving other forms of immunotherapy, such as ICI, or possibly with chemotherapy, also known to depend on intratumoral CTLs, both in bladder cancer and possibly potentially additional malignancies. In accordance with this possibility, our recent clinical trials involving systemic blockade of COX2 (oral celecoxib), combined with the local-or systemic administration of the chemokine-modulating (CKM) regimen involving a TLR3 ligand (rintatolimod) and IFNα (which inhibits EP2 and EP4 expression and PGE2-driven CREB phosphorylation [106]), resulted in an intratumoral shift from Treg-attracting to CTL-attracting chemokines and local enhancements (up to 10-fold [148]) of the CTL markers in the TME of ovarian and breast cancer patients [148][149][150].…”