Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis
Details
Publication Year 2022-10-11,Volume 41,Issue #2,Page 111479
Journal Title
Cell Reports
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.
Publisher
Cell Press
Keywords
CP: Cancer; CP: Immunology; desmoplasia; drug resistance; hematopoietic cell kinase; immune suppression; immunotherapy; myeloid cells; pancreatic cancer; tumor microenvironment
WEHI Research Division(s)
Immunology; Advanced Technology And Biology
PubMed ID
36223746
Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2022.111479
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-10-14 09:03:10
Last Modified: 2022-10-14 09:08:26
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