Article ; Online: Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer.
2023 Volume 13, Issue 6, Page(s) 1428–1453
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Humans ; Neutrophils ; Receptors, Tumor Necrosis Factor, Type II/therapeutic use ; Proto-Oncogene Proteins p21(ras)/genetics ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Inflammation/genetics ; Tumor Microenvironment/physiology ; Chemokine CXCL1/genetics ; Pancreatic Neoplasms | |||||
| Chemical Substances | Receptors, Tumor Necrosis Factor, Type II ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; CXCL1 protein, human ; Chemokine CXCL1 | |||||
| Language | English | |||||
| Publishing date | 2023-03-13 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural | |||||
| ZDB-ID | 2625242-9 | |||||
| ISSN | 2159-8290 ; 2159-8274 | |||||
| ISSN (online) | 2159-8290 | |||||
| ISSN | 2159-8274 | |||||
| DOI | 10.1158/2159-8290.CD-22-1046 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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