An Organoid Approach to Target Her2/PD‐L1 Positive Gastric Cancers

Abstract

BackgroundTumors can evade immune surveillance by expressing ligands such as programmed cell death 1 (PDL‐1) which interacts with PD‐1 or CTLA‐4, respectively, on CD8+ cytotoxic T lymphocytes (CTLs). These interactions inhibit CTL proliferation, survival, and effector function subsequently leading to immune evasion and cancer persistence. Despite that 40% of gastric cancers express PD‐L1, the response rate to immunotherapy is only 30%. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several metastatic cancers, including gastric. Half of PD‐L1‐positive gastric cancers co‐express HER2, but whether HER2‐induced PD‐L1 sustains tumor cell immune evasion has not been determined.HypothesisThe current research tests the hypothesis that targeted anti‐HER2 and immune checkpoint inhibition may provide synergistic effects in gastric cancer treatment.MethodsPatient‐derived gastric cancer organoids, generated from resected tumor tissues or biopsies were co‐cultured with cytotoxic T lymphocytes (CTLs) and tumor antigenloaded dendritic cells and myeloid‐derived suppressor cells (MDSCs).ResultsWhile PD‐L1‐positive tumor organoids co‐expressed HER2, pharmacological inhibition and gene knockdown of HER2 resulted in decreased PD‐L1 expression in tumor organoids. Within the organoid/immune cell co‐culture, decreased PD‐L1 expression in patient‐derived gastric cancer organoids correlated with a significant increase in CTL proliferation and survival, leading to cancer cell death. Similar results were within the co‐culture were observed in response to Nivolumab treatment. MDSCs within the co‐culture counteracted the inhibitory effects of Her2 inhibition by Mubritinib and Nivolumab.ConclusionThus, HER2‐induced PD‐L1 may contribute to tumor immune evasion. Organoid/immune cell co‐cultures may be used to effectively screen for targeted therapy in individual gastric cancer patients. Therapeutic anti‐HER2 antibody and, immune checkpoint inhibition, as well as depletion of MDSCs, may provide synergistic effects in gastric cancer treatment.Support or Funding Information• NIH NIDDK R01DK083402‐08 (Zavros)NIH 1U19AI116491‐01, (PIs: Weiss and Wells, Zavros Project Leader 1