Exploring the differences in the tumor microenvironment and immuno-oncologic targets in pancreatic ductal adenocarcinomas (PDAC) according to KRAS mutational status

Abstract

Background: The majority of pancreatic ductal adenocarcinomas (PDACs) are driven by mutant (mt) KRAS. How mt KRAS and co-driver mutations affect the immune cell (IC) landscape of PDAC remains uncertain. Herein, we characterize the types of IC in the PDAC tumor microenvironment (TME) and the prevalence of immuno-oncologic (IO) biomarkers by genomic and transcriptomic analysis in the context of KRAS status. Materials and methods: 4142 PDAC and 3727 colorectal cancer (CRC) cases with KRAS mt were analyzed using next-generation DNA sequencing, immunohistochemistry, and whole-transcriptome RNA sequencing. Microsatellite instability and deficiency in mismatch repair (MSI-H/dMMR) and tumor mutational burden (TMB) were also assessed. Results: We found KRAS mt in 81% of PDAC, with the most common variant being G12D in PDAC, and fewer cases of KRAS mt were co-expressed with the predictive IO marker MSI-H/dMMR than KRAS-wild-type (wt). However, KRASG12D, KRASG12V, and KRASQ61 mutations had significantly lower TMB than KRAS wt tumors in PDAC. The IC environment of KRAS mt PDAC showed significant differences in nearly all IC types; a similar pattern was observed in CRC but was less pronounced. Conclusions: Therapeutic IO targets like programmed death-ligand 1 are enriched in pancreatic adenocarcinoma cases harboring specific targetable variants of KRAS mt PDAC. Better understanding of the TME could lead to tailored immunotherapeutic strategies to overcome these barriers in KRAS mt PDAC, possibly in combination with molecularly targeted treatment strategies.

Keywords

• pancreatic cancer
• pancreatic adenocarcinoma
• KRAS
• genomics
• tumor microenvironment