Secretory leukocyte proteinase inhibitor: A key player in the dialogue between the tumor and its microenvironment in pancreatic cancer patients

CHULUYAN, EDUARDO HECTOR; AMBROSI, NELLA; FRAUNHOFFER NICOLAS A.; CARO, FIORELLA; REMOLINS, CARLA; REITERI, MACARENA; GUERRIERI, DIEGO; SOUBEYRAN, PHILIPPE; GAYET, ODILE; ROQUES, JULIE; DUSETTI, NELSON J.; ICARDONA, CLAUDIO; IOVANNA, JUAN

Simposio; ASCO Gastrointestinal Cancers Symposium; 2022

Background: Secretory leukocyte proteinase inhibitor (SLPI) is a non-glycosylated pleiotropic protein with anti-protease, microbicidal, healing, anti-inflammatory and immunomodulatory activity. Previous studies have shown that SLPI is associated with pancreatic tumor progression by promoting cancer cell survival and proliferation. However, SLPI can also act on the tumor microenvironment to affect the local immune response. In the present work we evaluate the role of SLPI in patients with pancreatic cancer and its activity as a tumor escape factor from the immune response. Methods: Serum levels of SLPI was measured in pancreatic cancer patients by sandwich ELISA. RNA-seq was performed on 76 patient-derived xenografts (PDX) and we computed independent component analysis focusing the study on the component that best correlated with SLPI gene. Secretome analysis was performed on 38 different cell lines cells culture derived from PDX. Human monocytes were isolated and differentiated into immature dendritic cells in the presence or absence of SLPI or in the presence of a pancreatic tumor cell line that did or did not express SLPI. Results: The frequency distribution of serum SLPI values showed patients with low and high SLPI value (cut-off value 61.5 ng/ml). Most patients with high serum SLPI concentration had unresectable tumors. There was an indirect association between serum SLPI levels and the time of disease recurrence. The transcriptome analysis showed that expression of SLPI is associated with immune and cancer functional clusters. The analysis of the secretome showed that SLPI was present in all cell lines from PDX. The heat map of the secretome exhibited that SLPI was directly associated with factors described in tumor microenvironment and related with tumor immune evasion mechanisms, such as CSF1, SECTM1, LGALS3, IL1RN, CD59, CD55, CD46, Fas, PVR, PVRL2. Remarkably, the closest group associated with SLPI was CSF1. The latter contributes to the depressed function of antigen-presenting cells, as a result of skewed differentiation of monocytes towards macrophage-like cells rather than dendritic cells. Furthermore, in vitro experiments demonstrated that SLPI or SLPI-producing pancreatic tumor cell lines impaired the differentiation of human monocytes towards dendritic cells and their immunostimulatory capacity. Conclusions: These results suggest that SLPI may contribute to the immunosuppressive microenvironment of pancreatic cancer by acting as a tumor immune evasion factor. Clinically, this SLPI activity could be reflected in the association of the serum SLPI value with disease recurrence or progression.