RNF43-mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses and Prolonged Survival in Pancreatic Adenocarcinoma.

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RNF43-mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here we undertake a detailed assessment of RNF43-mutations in PDAC. 313 PDACs [308 microsatellite stable (MSS) and five instable (MSI) cases] underwent next generation sequencing (Oncomine TML-Assay, ThermoFisher). Spatial analyses (Nanostring) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used do define spatial compartments (tumor: Pancytokeratin+/CD45- and leukocytes: Pancytokeratin-/CD45+). Each 20 PDACs with (RNF43mut) and without (RNF43wt) RNF43-mutations, underwent multiplex immunofluorescence analysis to determine immune status. 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA-sequencing to assign into molecular subtypes. Overall, 24 RNF43-mutations were identified (22 MSS-PDACs and 2 MSI-PDACs). The incidence of RNF43-mutations in MSS-PDACs (7.1%) was consistent with the TCGA (6.7%). However, RNF43-mutations were more frequent among MSI-PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher TMB-values (5.5 Mut/mb versus 1.67 Mut/mb, p<0.01) and significantly longer overall survival (OS; 47 versus 18 months, p<0.0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+T lymphocytes, dendritic cells (DC) and B lymphocytes (p<0.001 respectively) and an upregulation of ITGAX, CD11c, CD8 and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs show high TMB-values suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.

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