Unveiling the differences in tumor immune microenvironment between <i>KRAS</i> -wildtype and <i>KRAS</i> -mutant pancreatic ductal adenocarcinoma.

Abstract

4154 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a dismal prognosis despite advances in treatment. PDAC is characterized by a dense stromal environment with suppressed anti-tumor immunity that contributes to treatment resistance. Oncogenic KRAS mutations are present in &gt; 90% of PDACs and are known to play a role in modulating the tumor immune microenvironment (TME). In this study, we examined the differences in TME components between KRAS -mutant (m) and KRAS -wildtype (wt) PDACs. Methods: Comprehensive genomic and immune profiling (CGIP), including the RNA-seq based gene expression assessment of 395 immune-associated genes, was performed on 311 PDAC patient samples. Gene expression signatures of tumor immunogenicity (TIGS) and cell proliferation were calculated by averaging the gene expression ranks of 161 immune-associated genes and 10 proliferation genes, respectively. The normalized gene expression rank of 22 immune checkpoint genes and 17 cancer testis antigen (CTA) genes were also calculated. DNA-seq was used to identify KRAS mutations and to calculated tumor mutational burden (TMB). Continuous variables were compared between subgroups using the Wilcoxon Rank-Sum test and categorical variables were compared between groups using the Chi Squared test. For statistical significance, p &lt; 0.05 was required. Results: The cohort consisted of 311 PDAC patient samples, comprising 159 females (51.1%) and 152 males (48.9%) with a median age at testing of 69.3 years (38.7-92.6). A total of 264 specimens (84.9%) exhibited a KRAS mutation, with the most common being G12D and G12V while 47 (15.1%) had KRAS -wt tumors. No difference in TIGS, CP, or TMB was observed between KRAS -wt and KRAS -m tumors. KRAS -wt tumors exhibited greater expression of 12 of 17 tested CTAs than KRAS -m tumors, including GAGE13 (p = 0.004) NY-ESO-1 (p = 0.01), MAGEA3 (p = 0.01), and LAGE1A (p = 0.01). Analysis of the gene expression of 22 immune checkpoint genes showed no difference for most of the genes, though there was higher expression of PD-1 (p = 0.04) and CD27 (p = 0.03) seen in KRAS -wt compared to KRAS -m tumors. Conclusions: KRAS -wt PDACs exhibited greater expression of cancer testis antigen genes compared to KRAS -m tumors, suggesting potential therapeutic susceptibility to immunotherapy and adoptive cell therapies leveraging the expression of CTAs as targets. Assessment of KRAS status and immunotherapy susceptibility may support future clinical trial selections for therapies targeting the complex interplay of genomic and immune components of pancreatic cancer.