Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.

Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models

“…We found that the Interleukin 17 (IL17) signaling pathway was the highest upregulated Reactome pathway in p53 -GOF papillomas compared to both p53 -LOF and p53 -WT papillomas ( Figure 6 C and Table S6 ). Although the functional significance of IL17 signaling in oral cancer immunoprevention needs further investigation, recent studies have linked IL17 to resistance to immune checkpoint inhibitors in pancreatic cancer [ 42 ].…”

“…IL17 signaling was the leading pathway found to be upregulated in p53 -GOF papillomas. This finding could be relevant for oral cancer immunoprevention, as IL17 signaling is emerging as a potent immunosuppressive mechanism that promotes resistance to immune checkpoint blockade, although the mechanisms underlying these effects are still poorly understood [ 42 ]. Our data suggest that p53 -GOF mutations could promote an immunosuppressive microenvironment by upregulating IL17 signaling.…”

Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines

“…High IL17A gene expression also correlated with worse survival outcomes for pancreatic ductal adenocarcinoma patients [73]. In the spontaneous, genetically engineered KPC (pancreas-specific conditional mutation of Kras and Tp53) pancreatic cancer mouse model, co-blockade with antibodies targeting IL-17 and the IL-17 receptor in combination with anti-PD-1 Ab or anti-CTLA-4 Ab reduced tumor burden that was mediated by increased CD8 + T cells in the TME [73]. In addition, an abundance of Th17 cells reside in the gut, and their presence and functionality can be modified in response to microbiota [74].…”

“…By contrast, Il17 −/− mice were resistant to 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogen-induced tumor initiation, accompanied by increased IFN-γ-producing CD8 + T cells in the inflamed skin compared to WT mice [72]. High IL17A gene expression also correlated with worse survival outcomes for pancreatic ductal adenocarcinoma patients [73]. In the spontaneous, genetically engineered KPC (pancreas-specific conditional mutation of Kras and Tp53) pancreatic cancer mouse model, co-blockade with antibodies targeting IL-17 and the IL-17 receptor in combination with anti-PD-1 Ab or anti-CTLA-4 Ab reduced tumor burden that was mediated by increased CD8 + T cells in the TME [73].…”

Neutrophils as Orchestrators in Tumor Development and Metastasis Formation

“…Except from their established role in host-pathogen interactions ( 42 ), NETs modulate cancer-associated procoagulant activity ( 44 ) and promote tumor growth ( 45 , 46 ) by including tumor-promoting components such as MMP-9, cathepsin G ( 47 ) and neutrophil elastase ( 45 , 46 ). In addition, presence of NETs in patients diagnosed with cancer has been associated with poor prognosis ( 48 ) and blockade of IL17-mediated NET generation resulted in increased responsiveness to immune checkpoint blockade in pancreatic ductal adenocarcinoma ( 49 ).…”