Background & Aims

Pancreatic ductal adenocarcinoma (PDA) initiation and progression is accompanied by an immunosuppressive inflammatory response. Here, we evaluated the immunomodulatory role of chemosensory signaling in metaplastic tuft cells (MTCs) by analyzing the role of GNAT3, a gustatory pathway G-protein expressed by MTCs, during PDA progression.

Methods

Gnat3-null (Gnat3^-/-) mice were crossbred with animals harboring a Cre-inducible Kras^LSL-G12D/+ allele with either Ptf1a^Cre/+ (KC) or tamoxifen-inducible Ptf1a^CreERT/+ (KC^ERT) mice to drive oncogenic KRAS expression in the pancreas. Ex vivo organoid conditioned media generated from KC and Gnat3^-/-;KC acinar cells was analyzed for cytokine secretion. Experimental pancreatitis was induced in KC^ERT and Gnat3^-/-;KC^ERT mice to accelerate tumorigenesis followed by analysis using mass cytometry and single-cell RNA sequencing. To study PDA progression, KC and Gnat3^-/-;KC mice were aged to morbidity or 52-weeks.

Results

Ablation of Gnat3 in KC organoids increased release of tumor-promoting cytokines in conditioned media, including CXCL1 and CXCL2. Analysis of Gnat3^-/-;KC^ERT pancreata found altered expression of immunomodulatory genes in Cxcr2 expressing myeloid-derived suppressor cells (MDSC) and an increased number of granulocytic MDSCs (gMDSC), a subset of tumor promoting MDSCs. Importantly, expression levels of CXCL1 and CXCL2, known ligands for CXCR2, were also elevated in Gnat3^-/-;KC^ERT pancreata. Consistent with the tumor-promoting role of MDSCs, aged Gnat3^-/-;KC mice progressed more rapidly to metastatic carcinoma compared to KC controls.

Conclusions

Compromised gustatory sensing, achieved by Gnat3 ablation, enhanced the CXCL1/2 – CXCR2 axis to alter the MDSC population and promoted the progression of metastatic PDA.