KL2 Scholar Scope: Macrophage Regulation of Peritoneal Carcinomatosis in Gastric Adenocarcinoma

Macrophage regulation of peritoneal carcinomatosis in gastric adenocarcinoma Gastric cancer remains a lethal global health concern. It is the 3rd most common leading cause of cancer related mortality worldwide. The peritoneum is the most common site of synchronous and metachronous metastasis, accounting for 60% of recurrences. Peritoneal carcinomatosis results in 65% of gastric cancer associated deaths, resulting in median overall survival of 3-6 months with standard of care chemotherapy. Programmed cell death protein 1 (PD-1) checkpoint-based immunotherapy has produced unprecedented results in metastatic gastric cancer, as the only modality to effectively increase overall survival to 13 months. However, most patients remain resistant to immune check-point blockade (ICB). Therefore, understanding mechanisms of resistance, biomarker selection and nominating combinatorial therapies to bolster immune responses remains a clinically unmet need. In its resting state, the peritoneal cavity harbors a rich milieu of immune cells, which have been implicated in response to infection and inflammation. Macrophages are the predominant antigen presenting cells in the peritoneum initiating innate and adaptive responses. In gastric cancer, infiltration of tumor associated macrophages in the peritoneum portends a poorer prognosis. Interleukin 8/ C-X-C motif chemokine ligand 8 (IL8/CXCL8) is a cytokine secreted by gastric tumors with pleotropic effects on various cell types, including macrophages. Its expression is associated with poor survival in gastric cancer and limited response to ICB. In a Phase 1 trial of advanced solid organ tumors, anti-IL8/CXCL8 monotherapy was safe and tolerable. Thus, we seek to understand how gastric cancer cells pervert anti-tumor immunity and promote peritoneal carcinomatosis via macrophage dependent mechanisms. We hypothesize that tumoral IL8/CXCL8 secretion promotes tolerogenic macrophage transformation, macrophage mediated T cell immunosuppression and ICB resistance.