KRAS drives immune evasion in a genetic model of pancreatic cancer

Abstract

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.

Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

“…In 2019, we reported that KRAS mutant cancer cells with a gain-of-function p53 mutation can “educate” adjacent CAFs via short and long range NFκB/TNFα signalling, driving the establishment of a pro-metastatic and chemoresistant environment by secreting perlecan (a basement membrane protein) [ 29 ] ( Figure 2 b). Likewise, Novo et al, (2018) reported that pancreatic cancer cells with a mutant p53 phenotype can activate fibroblasts to be pro-invasive via exosomal secretion of a sialylated glycoprotein called podocalyxin (PODXL), while p53 null-derived exosomes could not [ 75 ] ( Figure 2 b). Strikingly, it was also shown that exosome-derived PODXL affects ECM organisation and remodeling in the lungs of mice enhancing metastatic colonization [ 75 ].…”

“…Likewise, Novo et al, (2018) reported that pancreatic cancer cells with a mutant p53 phenotype can activate fibroblasts to be pro-invasive via exosomal secretion of a sialylated glycoprotein called podocalyxin (PODXL), while p53 null-derived exosomes could not [ 75 ] ( Figure 2 b). Strikingly, it was also shown that exosome-derived PODXL affects ECM organisation and remodeling in the lungs of mice enhancing metastatic colonization [ 75 ]. These studies demonstrate the influence of p53 mutational status on disease progression and therapeutic response further highlighting the heterogeneous nature and influence of different stromal populations on tumor behavior [ 28 , 29 ].…”

“…( a ) Reciprocal Kras G12D signalling between tumor and stromal cells regulates signalling axes, which influence cancer cell proliferation and apoptosis [ 74 ]. ( b ) Cancer cells with distinct p53 mutations can modulate neighbouring and distant fibroblasts to establish a fibrotic, pro-invasive and pro-metastatic environment [ 29 , 75 ]. ( c ) TGF-β signalling via STAT3 increases desmoplasia and stiffening of the tumor ECM and is fundamental in the distinct formation of myCAFs and iCAFs.…”

Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer

“…Oncogenic KRAS is a key mediator of immune suppression in PDA. A recent study using scRNA-seq approaches and TCGA data analysis suggest greater immune infiltration in KRAS independent and KRAS-low tumors compared to KRAS dependent and KRAS-high groups ( 33 ). In this model, inactivation of mutant Kras in PDA cells did not affect their tumorigenic capacity, but led to failure to evade the host immune system ( 33 ).…”

“…A recent study using scRNA-seq approaches and TCGA data analysis suggest greater immune infiltration in KRAS independent and KRAS-low tumors compared to KRAS dependent and KRAS-high groups ( 33 ). In this model, inactivation of mutant Kras in PDA cells did not affect their tumorigenic capacity, but led to failure to evade the host immune system ( 33 ). The authors determined that KRAS knockout (KO) PDA cells had a striking up-regulation of major histocompatibility complex I (MHC I) genes compared with KRAS intact control cells, underlying increased susceptibility to anti-tumor immunity.…”