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Exploring the differences in the tumor microenvironment and immuno-oncologic targets in pancreatic ductal

E B Faber1,2, Y Baca3, J Xiu3

  • 1Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis.

ESMO Gastrointestinal Oncology
|February 6, 2026
PubMed
Abstract

Insights

Mutant KRAS drives most pancreatic cancers, altering the immune cell landscape. Understanding these changes and biomarkers like MSI-H/dMMR can guide targeted immunotherapies for KRAS-mutant PDAC.

Area of Science:

  • Oncology
  • Cancer Genomics
  • Immunology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by mutations in the KRAS gene.
  • The impact of KRAS mutations and co-occurring mutations on the immune cell (IC) landscape within the PDAC tumor microenvironment (TME) is not fully understood.
  • Characterizing immune cell infiltration and immuno-oncologic (IO) biomarkers in relation to KRAS status is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the relationship between KRAS mutation status and the immune cell landscape in PDAC.
  • To identify prevalent IO biomarkers in PDAC and correlate them with KRAS mutational status.
  • To explore potential therapeutic strategies based on the genomic and transcriptomic profiles of PDAC.

Main Methods:

  • Analysis of 4142 PDAC and 3727 colorectal cancer (CRC) cases using next-generation DNA sequencing.
  • Assessment of whole-transcriptome RNA sequencing, immunohistochemistry, microsatellite instability (MSI-H/dMMR), and tumor mutational burden (TMB).
  • Genomic and transcriptomic characterization of the PDAC TME in the context of KRAS status.

Main Results:

  • KRAS mutations were found in 81% of PDAC cases, with G12D being the most common variant.
  • KRAS-mutant PDAC showed significantly lower TMB compared to KRAS wild-type tumors.
  • Distinct immune cell infiltration patterns were observed in KRAS-mutant PDAC compared to KRAS wild-type, with similar but less pronounced differences in CRC.
  • The predictive IO marker MSI-H/dMMR was less frequent in KRAS-mutant PDAC than in KRAS wild-type.

Conclusions:

  • Specific KRAS variants in PDAC are associated with unique immune cell microenvironments and TMB levels.
  • Therapeutic IO targets, such as programmed death-ligand 1, are enriched in specific KRAS-mutant PDAC cases.
  • Understanding the TME in KRAS-mutant PDAC is essential for developing tailored immunotherapeutic and molecularly targeted treatment strategies.
Keywords:
KRASgenomicspancreatic adenocarcinomapancreatic cancertumor microenvironment

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