Integrated tissue and secretome profiling identifies an IL-6/IL-8-dominant immune phenotype in peritoneal carcinomatosis

Background: Peritoneal carcinomatosis (PC) is a late manifestation of abdominopelvic malignancies, often resistant to current treatments due to an incomplete understanding of its biological drivers within the peritoneal immune microenvironment. This study aimed to identify actionable therapeutic targets for PC by analyzing peritoneal soluble mediators and cellular composition in patients. Building on existing evidence implicating IL-8 as a critical mediator of tumor-associated inflammation and immunosuppression in other cancers and preliminary data in PC, the study also evaluated IL-8 pathway inhibition in a preclinical model. Methods: Peritoneal tissue and fluid were collected from three patient groups: patients without benign conditions (n=15), cancer without PC (n=30), and confirmed PC (n=41). Immunohistochemistry was used to quantify immune cells in tissue and Luminex panels to analyze immune, inflammatory, and growth factors in peritoneal fluid. Statistical analyses identified group differences, correlations with disease burden (Peritoneal Cancer Index - PCI), and overall survival (OS). To assess therapeutic tractability of IL-8 axis blockade, a bioluminescent CT26-luc murine PC model was treated daily with the CXCR2 antagonist AZD5069 (100 mg/kg) or saline from day 0-9, with serial IVIS imaging, body-weight monitoring, and survival tracking through day 11. Results: PC tissue exhibited increased immune cell infiltration compared to non-PC groups, including elevated mast cells, neutrophils, CD4⁺ T cells, CD14⁺ monocytes, CD20⁺ B cells, and CD138⁺ plasma cells. Secretomic analysis of peritoneal fluid in PC revealed a dominant IL-6/IL-8-centered inflammatory signature, with increased GRO, IL-6, IL-8, CXCL10, IL-10, and TGF-beta. This pattern supports pro-angiogenic, immunosuppressive, and stromal-activation signaling. Densities of CD4⁺, CD14⁺, CD20⁺, and CD138⁺ cells positively correlated with PCI, indicating progressive immune-stromal co-evolution with tumor burden. In human samples, neutrophil infiltration correlated with worse OS, while CD1a⁺ dendritic cell enrichment correlated with improved OS, underscoring the clinical relevance of the immunologic findings. In the murine model, AZD5069 demonstrated a therapeutic effect in 4 of 10 treated mice, suggesting potential efficacy of IL-8-axis targeting in specific patient subsets. Conclusion: PC is characterized by distinct immune cell infiltration and a significant IL-6/IL-8 cytokine network. Both neutrophil infiltration and the IL-6/IL-8 axis are associated with disease burden and patient survival, highlighting the IL-6/IL-8 axis as a relevant therapeutic target. Preclinical evidence supports its potential in specific patient groups. Further research is needed to identify predictive biomarkers for treatment response and translate these findings into clinical strategies.