| Popis: |
Aim: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is highly immune suppressive with modest T-cell infiltration, and only rarely responds to immune checkpoint inhibition (ICI) therapy. Our aim was to clarify the molecular basis underlying the immune suppressive properties of PDAC.Background: Mutations in both KRAS and TP53 genes are characteristic of PDAC. A major target of KRAS/TP53 double mutations is the ARF6-AMAP1 pathway, which promotes the fibrosis, acidosis, invasion, and immune evasion of cancer cells. KPC cells are a genetically well-defined mouse cell model of human PDAC bearing Kras/Trp53 mutations, and express Arf6 and Amap1 at high levels.Findings: Intact KPC cells predominantly expressed immune suppressive chemokines, such as Cxcl12 and Cxcl5, but when Amap1 was silenced, immune surveillance chemokines, such as Cxcl10 and Ccl5 became predominant. A similar, albeit fragmented, chemokine switching was observed in human PDAC cells, and this mechanism appeared to be used in the normal pancreas of humans and mice. The silencing of Amap1 in KPC cells significantly changed the types and numbers of tumor infiltrating lymphocytes to be less favorable for immune evasion.Conclusions: Many PDAC cells appear to have a hitherto unidentified mechanism of malignancy, by which they can change the types of chemokines that they produce to be favorable for immune evasion. The ARF6-AMAP1 pathway is integral to this chemokine switching. Hence, this malignancy appears to be the result of KRAS/TP53 double mutations, which are not common in other types of cancer unless they are in the advanced stages. Our results are consistent with our previous findings that blockade of the ARF6- AMAP1 pathway significantly improves the efficacy of ICI therapy. |
