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Title: Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis.
Austin Authors: Poh, Ashleigh R;O'Brien, Megan;Chisanga, David;He, Hong ;Baloyan, David;Traichel, Jasmin;Dijkstra, Christine ;Chopin, Michaël;Nutt, Stephen;Whitehead, Lachlan;Boon, Louis;Parkin, Ashleigh;Lowell, Clifford;Pajic, Marina;Shi, Wei;Nikfarjam, Mehrdad ;Ernst, Matthias 
Affiliation: Department of Computing and Information Systems, University of Melbourne, Melbourne, VIC 3010, Australia
Olivia Newton-John Cancer Research Institute
The Walter and Eliza Hall Institute and University of Melbourne Department of Medical Biology, Melbourne, VIC 3052, Australia
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
Department of Surgery, University of Melbourne and Austin Health, Melbourne, VIC 3084, Australia
St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia
Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg 79104, Germany..
JJP Biologics, Warsaw 00-728, Poland..
University of California San Francisco, San Francisco, CA 94131, USA..
Issue Date: 11-Oct-2022
Publication information: Cell Reports 2022; 41(2): 111479
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.
DOI: 10.1016/j.celrep.2022.111479
Journal: Cell Reports
PubMed URL: 36223746
Type: Journal Article
Subjects: CP: Cancer
CP: Immunology
drug resistance
hematopoietic cell kinase
immune suppression
myeloid cells
pancreatic cancer
tumor microenvironment
Appears in Collections:Journal articles

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