Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> A well-characterized PDAC cohort (<i>n</i> = 110) underwent next-generation sequencing with a hot spot 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 8th edition, 2017), survival, and epithelial-mesenchymal transition (EMT)-like tumor budding.<b>Results:</b> Three PDAC subtypes were identified: the "immune escape" (54%), poor in T and B cells and enriched in FOXP3⁺ regulatory T cells (Treg), with high-grade budding, frequent <i>CDKN2A</i>, <i>SMAD4</i>, and <i>PIK3CA</i> mutations, and poor outcome; the "immune rich" (35%), rich in T and B cells and poorer in FOXP3⁺ Tregs, with infrequent budding, lower <i>CDKN2A</i> and <i>PIK3CA</i> mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (<i>STK11</i> and <i>ATM</i>), and the best outcome; and the "immune exhausted" (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high <i>PIK3CA</i> mutation rate and a microsatellite-unstable subpopulation with a high prevalence of <i>JAK3</i> mutations. The combination of low budding, low stromal FOXP3 counts, presence of TLTs, and absence of <i>CDKN2A</i> mutations confers significant survival advantage in patients with PDAC.<b>Conclusions:</b> Immune host responses correlate with tumor characteristics, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance. <i>Clin Cancer Res; 24(18); 4444-54. ©2018 AACR</i><i>See related commentary by Khalil and O'Reilly, p. 4355</i>.