Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

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.
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Details

Published: Mar 22, 2023
Vol/Issue: 13(6)
Pages: 1428-1453

Authors

A

Anna Bianchi

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

I

Iago De Castro Silva

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

N

Nilesh U. Deshpande

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

S

Samara Singh

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

S

Siddharth Mehra

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

V

Vanessa T. Garrido

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

X

Xinyu Guo

2Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

L

Luis A. Nivelo

3Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.

D

Despina S. Kolonias

4Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

S

Shannon J. Saigh

5Sylvester Comprehensive Cancer Center, Miami, Florida.

E

Eric Wieder

5Sylvester Comprehensive Cancer Center, Miami, Florida.

C

Christine I. Rafie

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.; 3Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.

A

Austin R. Dosch

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

Z

Zhiqun Zhou

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

O

Oliver Umland

6Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida.

H

Haleh Amirian

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

I

Ifeanyichukwu C. Ogobuiro

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

J

Jian Zhang

4Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Y

Yuguang Ban

7Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida.

C

Carina Shiau

8Center for Systems Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

N

Nagaraj S. Nagathihalli

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.; 5Sylvester Comprehensive Cancer Center, Miami, Florida.

E

Elizabeth A. Montgomery

9Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida.

W

William L. Hwang

8Center for Systems Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

R

Roberta Brambilla

10The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida.

K

Krishna Komanduri

11Department of Medicine, University of California San Francisco Health, San Francisco, California.

A

Alejandro V. Villarino

3Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.

E

Eneda Toska

12Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

B

Ben Z. Stanger

13Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

D

Dmitry I. Gabrilovich

14AstraZeneca, Gaithersburg, Maryland.

N

Nipun B. Merchant

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.; 5Sylvester Comprehensive Cancer Center, Miami, Florida.

J

Jashodeep Datta

1Division of Surgical Oncology, Dewitt Daughtry Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.; 5Sylvester Comprehensive Cancer Center, Miami, Florida.

Funding

National Cancer Institute Award: P30CA240139

National Institutes of Health Award: UL1TR002736

Elsa U. Pardee Foundation Award: AWD-007035

American College of Surgeons

Society of Surgical Oncology

Association for Academic Surgery

Cite This Article

Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, et al. (2023). Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer. Cancer Discovery, 13(6), 1428-1453. https://doi.org/10.1158/2159-8290.cd-22-1046

Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

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