Dual inhibition of tumor cells and tumor-associated neutrophils by anti-CXCR2 antibodies suppresses tumor growth and augments immunotherapy efficacy in ARID1A-deficient pancreatic cancer.

Authors

Tzu-Lei Kuo, Kuan-Chung Hsiao, Ko-Jiunn Liu, Li-Tzong Chen, Wen-Chun Hung

Published in

Cancer immunology, immunotherapy : CII. Jul 21, 2026. Epub Jul 21, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to immune checkpoint blockade (ICB) due to its highly immunosuppressive tumor microenvironment. How to switch the "immune-cold" microenvironment to "immune hot" one is a clinical unmet need. We recently generated a genetically engineered PDAC mouse model (KAR) by combining K-Ras mutation and AT-rich interactive domain-containing protein 1A (ARID1A) inactivation in the pancreas. Compared to the KPC (K-Ras mutation + p53 inactivation) tumors, KAR tumors express higher C-X-C chemokine receptor 2 (CXCR2) and have more CXCR2⁺ neutrophils infiltration. Our previous study demonstrated that activation of CXCR2 by its cognate ligands promotes proliferation and drug resistance in PDAC cells. In addition, increase in tumor-associated neutrophils and high neutrophil-to-lymphocyte ratio are associated with worse prognosis in PDAC patients. Here, we developed a monoclonal antibody against human CXCR2 (huCXCR2-Ab) and tested its therapeutic effect in cells and in animals. Treatment with huCXCR2-Ab inhibited IL-8-induced downstream signaling, and the proliferation of human PDAC cancer cells. In addition, huCXCR2-Ab suppressed PDAC growth in an orthotopic nude mouse model. We next developed a monoclonal antibody against mouse CXCR2 (muCXCR2-Ab) and investigated its immune regulatory effect in vivo. We showed that muCXCR2-Ab reduced tumor burden, increased CD8⁺ T-cell infiltration, and decreased immunosuppressive neutrophils in the KAR mice. Moreover, muCXCR2-Ab augments the therapeutic efficacy of anti-PD-L1. Thus, dual targeting of CXCR2⁺ tumor cells and tumor-associated neutrophils remodels tumor microenvironment and enhances immunotherapy response in ARID1A-deficient PDAC, providing a new strategy for precision therapy of PDAC.

PMID:
42479087
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.

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