Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance

Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. Experimental Design: A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with a hotspot cancer panel, while Next-generation Tissue-Microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM) and DNA mismatch-repair proteins. Previous data on FOXP3 were integrated. Immune-cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8. 2017), survival and epithelial-mesenchymal-transition (EMT)-like tumor budding.  Results: Three PDAC-subtypes were identified: the "immune-escape" (54%), poor in T- and B-cells and enriched in FOXP3+Tregs, with high-grade budding, frequent CDKN2A- , SMAD4- and PIK3CA-mutations and poor outcome; the "immune-rich" (35%), rich in T- and B-cells and poorer in FOXP3+Tregs, with infrequent budding, lower CDKN2A- and PIK3CA-mutation rate and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11, ATM) and the best outcome; and the "immune-exhausted" (11%) with immunogenic microenvironment and two subpopulations: one with PD-L1-expression and high PIK3CA-mutation rate and a microsatellite-unstable subpopulation with high prevalence of JAK3-mutations. The combination of low budding, low stromal FOXP3-counts, presence of TLTs and absence of CDKN2A-mutations confers significant survival advantage in PDAC-patients. Conclusions:Immune host responses correlate with tumor characteristics leading to morphologically recognizable PDAC-subtypes with prognostic/predictive significance.

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