학술논문
Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer.
Document Type
article
Author
Bianchi, Anna; De Castro Silva, Iago; Deshpande, Nilesh; Singh, Samara; Mehra, Siddharth; Garrido, Vanessa; Guo, Xinyu; Nivelo, Luis; Kolonias, Despina; Saigh, Shannon; Wieder, Eric; Rafie, Christine; Dosch, Austin; Zhou, Zhiqun; Umland, Oliver; Amirian, Haleh; Ogobuiro, Ifeanyichukwu; Zhang, Jian; Ban, Yuguang; Shiau, Carina; Nagathihalli, Nagaraj; Montgomery, Elizabeth; Hwang, William; Brambilla, Roberta; Villarino, Alejandro; Toska, Eneda; Stanger, Ben; Gabrilovich, Dmitry; Merchant, Nipun; Datta, Jashodeep; Komanduri, Krishna
Source
Cancer Discovery. 13(6)
Subject
Language
Abstract
UNLABELLED: We have shown that KRAS-TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS-TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-KrasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms the trafficking and functional dynamics of neutrophils to overcome T-cell exclusion and controls tumor growth in a T cell-dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembrane TNF-TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell-neutrophil cross-talk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC. SIGNIFICANCE: By decoding connections between high-risk tumor genotypes, cell-autonomous inflammatory programs, and myeloid-enriched/T cell-excluded contexts, we identify a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic tumor microenvironments. This work offers a conceptual framework by which targeting context-dependent TNF signaling may overcome hallmarks of chemoresistance in pancreatic cancer. This article is highlighted in the In This Issue feature, p. 1275.