Expression of immune genes and a signature of PD-1 inhibition resistance in basal-like pancreatic adenocarcinoma (PDAC) subtypes.

Abstract

277 Background: PDAC is a lethal disease with poor survival even when detected at an early stage. Recurrence rates after surgical resection remain high. Recently, two distinct molecular subtypes of PDAC (basal-like and classical) have been identified with basal-like tumors demonstrating inferior outcomes. We hypothesize that differences in tumor immunogenicity may contribute to this aggressive biology and predict response to immune checkpoint inhibitors. Methods: RNA sequencing was performed on formalin-fixed paraffin embedded samples of 60 resected PDAC patients. We evaluated previously published immune gene expression signatures comprised of 1400 genes and used a single sample classifier to determine molecular subtypes. Results: Table 1 summarizes patient characteristics in our cohort. There were 35 classical and 25 basal-like tumors. PFS was significantly shorter in patients with basal-like compared to classical subtypes (9 vs 15 mo, p = 0.006). In a multivariable model with molecular subtype, lymph node and margin status, subtype was the only independent predictor of PFS (p=0.028). Unsupervised clustering identified two distinct immune groups that were associated with molecular subtypes (p=0.038) with higher expression of immune genes in basal-like tumors. Basal-like tumors were significantly associated with an immunosuppressive signature (p<0.001) and a signature associated with non-response to PD-1 inhibition in melanoma (p=0.001). Conclusions: This is the first study to show that basal-like pancreatic cancers are associated with increased immune gene expression and may help explain their inferior prognosis. We hypothesize that this reflects an increase in immunosuppressive cells in basal-like tumors that may predict decreased response to immune check point inhibitors. [Table: see text]