Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) continues to be an aggressive disease with an immunosuppressive tumor microenvironment, which is recalcitrant to most therapies. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been implicated in initiation of pancreatic premalignant lesions but its role in invasive PDAC has not been widely explored. We hypothesized that IL-17 triggers and sustains immunosuppression during PDAC. We employed pharmacological and genetic strategies to inhibit IL-17/IL-17RA signaling axis and characterized the tumor microenvironment with RNA sequencing, mass & flow cytometry and quantitative multiplex immunofluorescence. Our analysis revealed that IL-17 signaled through tumor cells to recruit neutrophils into the tumor microenvironment and spatially exclude cytotoxic CD8 T cells. Furthermore, IL-17 signaling in tumor cells triggered neutrophils to form extracellular traps (NETs), a primary mechanism mediating PDAC immunosuppression. Genetic or pharmacological inhibition of IL-17 overcame resistance to immune checkpoint blockade (PD-1, CTLA-4), in a CD8 T cell dependent manner. Inhibition of neutrophils or Padi4-dependent NETosis phenocopied IL-17 neutralization. Higher expression of IL-17 and PADI4 in human PDAC corresponded with poorer prognosis, according to TCGA data. Serum from PDAC patients had a higher capacity for NET formation and diminished ability for NET degradation in control neutrophils, in comparison to serum from healthy donors. In conclusion, the cross-talk of IL-17 with pancreatic cancer cells orchestrates neutrophil recruitment and activation of Padi4 dependent NETosis, ultimately resulting in spatial remodeling of the stroma and immunosuppression. IL-17 inhibition overcomes resistance to checkpoint blockade in a CD8 T cell dependent fashion. Clinical studies with IL-17 inhibitors and checkpoint blockade represent a promising novel combinatorial therapy for this lethal disease. Citation Format: Vidhi Chandra, Yu Zhang, Erick Riquelme, Prasanta Dutta, Pompeyo R. Quesada, Amanda Rakoski, Michelle Zoltan, Nivedita Arora, Seyda Baydogan, William Horne, Jared Burks, Hanwen Xu, Perwez Hussain, Huamin Wang, Sonal Gupta, Anirban Maitra, Jennifer M. Bailey, Seyed J. Moghaddam, Sulagna Banerjee, Ismet Sahin, Pratip Bhattacharya, Florencia McAllister. Interleukin 17 induced- neutrophil extracellular traps (NETs) mediate resistance to checkpoint blockade in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-014.
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