1. Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer.
- Author
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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, and Komanduri, Krishna
- Subjects
Humans ,Neutrophils ,Receptors ,Tumor Necrosis Factor ,Type II ,Proto-Oncogene Proteins p21(ras) ,Pancreatic Neoplasms ,Carcinoma ,Pancreatic Ductal ,Inflammation ,Tumor Microenvironment ,Chemokine CXCL1 - 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.
- Published
- 2023