Effect of PD-1 inhibition on macrophage population in human tissue cultures.

Abstract

463 Background: Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers (GC/EGJC) urge for reliable biomarkers. To further improve treatment outcomes, patients need targeted therapy based on clinically relevant biomarkers and predictive test systems for assessing individual drug susceptibility. We have previously established patient derived tissue cultures (PDTC) as a comprehensive ex-vivo drug testing system for GC/EGJC patients. Methods: The standardized PDTC) model was developed using tissue from surgical resection specimens to investigate response to the PD-1 inhibitor Nivolumab and the macrophage depriving bisphosphonates clodronate and zoledronic acid. Resident macrophage population (CD68, CD163), tumor proliferation (Ki67) and apoptosis (cPARP), as well as bulk gene expression data (nanoString technology) were analysed after 72 hours of PD-1 inhibition. Additionally, supernatants were collected, and cytokine concentrations are measured based on Luminex technology. Results: Macrophage depletion could lead to enhanced anti-tumoral effects in PDTCs after PD-1 inhibition. Gene signatures for Interferon γ-mediated inflammation and myeloid cell activity were identified and found to be relevant indicators for tissue response upon immune checkpoint inhibition. We observed alterations in cytokine and soluble surface marker concentrations, such as IL-8, IL-17A and IL-23 or PD-L2, LAG3 and CTLA4. Conclusions: Yielding an organotypic cell composition, we were able to demonstrate individual response patterns and immunological characteristics to identify responsiveness to PD-1 inhibition in GC and EGJC tissue. PDTCs are potent to define biological marker sets ex vivo and to differentiate and predict clinical patient response as well as their inherent immune cell capacity and plasticity.