Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis

Ashleigh R Poh; Megan O'Brien; David Chisanga; Hong He; David Baloyan; Jasmin Traichel; Christine Dijkstra; Michaël Chopin; Stephen Nutt; Lachlan Whitehead; Louis Boon; Ashleigh Parkin; Clifford Lowell; Marina Pajic; Wei Shi; Mehrdad Nikfarjam; Matthias Ernst

doi:10.1016/j.celrep.2022.111479

Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis

Cell Rep. 2022 Oct 11;41(2):111479. doi: 10.1016/j.celrep.2022.111479.

Authors

Ashleigh R Poh¹, Megan O'Brien¹, David Chisanga¹, Hong He², David Baloyan¹, Jasmin Traichel³, Christine Dijkstra¹, Michaël Chopin⁴, Stephen Nutt⁴, Lachlan Whitehead⁴, Louis Boon⁵, Ashleigh Parkin⁶, Clifford Lowell⁷, Marina Pajic⁸, Wei Shi⁹, Mehrdad Nikfarjam², Matthias Ernst¹⁰

Affiliations

¹ Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC 3084, Australia.
² Department of Surgery, University of Melbourne and Austin Health, Melbourne, VIC 3084, Australia.
³ Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg 79104, Germany.
⁴ The Walter and Eliza Hall Institute and University of Melbourne Department of Medical Biology, Melbourne, VIC 3052, Australia.
⁵ JJP Biologics, Warsaw 00-728, Poland.
⁶ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁷ University of California San Francisco, San Francisco, CA 94131, USA.
⁸ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
⁹ Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC 3084, Australia; Department of Computing and Information Systems, University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁰ Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Melbourne, VIC 3084, Australia. Electronic address: matthias.ernst@onjcri.org.au.

PMID: 36223746
DOI: 10.1016/j.celrep.2022.111479

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.

Keywords: CP: Cancer; CP: Immunology; desmoplasia; drug resistance; hematopoietic cell kinase; immune suppression; immunotherapy; myeloid cells; pancreatic cancer; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / genetics
Mice
Myeloid Cells / metabolism
Pancreatic Neoplasms* / pathology
Proto-Oncogene Proteins c-hck* / genetics
Tumor Microenvironment

Substances

Hck protein, mouse
Proto-Oncogene Proteins c-hck