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

Poh, Ashleigh; O'Brien, Megan; Chisanga, David; He, H; Baloyan, D; Traichel, J; Dijkstra, C; Chopin, M; Nutt, S; Whitehead, L; Boon, L; Parkin, A; Lowell, C; Pajic, M; Shi, Wei; Nikfarjam, M; Ernst, Matthias

doi:10.26181/21974978.v1

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

journal contribution

posted on 2023-01-30, 05:55 authored by Ashleigh PohAshleigh Poh, Megan O'BrienMegan O'Brien, David Chisanga, H He, D Baloyan, J Traichel, C Dijkstra, M Chopin, S Nutt, L Whitehead, L Boon, A Parkin, C Lowell, M Pajic, Wei ShiWei Shi, M Nikfarjam, Matthias ErnstMatthias Ernst

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.

Funding

This work was supported in parts through the Victorian State Government Operational Infrastructure Support and the National Health and Medical Research Council (NHMRC) of Australia project and development grants 1081373, 1092788, and 2014063. C.A.L. received funding from the UC Cancer Research Coordinating Committee (CRR-20-636450). M.E. received funding from Ludwig Cancer Research and is a NHMRC Investigator grant recipient (1173814). A.R.P. received support from 2018 Priority-driven Collaborative Cancer Research Scheme Grant (1157894) co-funded by Cancer Australia, Cure Cancer and Pancare Foundation; a Tour de Cure Early Career Seed Grant (RSP-060-18/19); and an Avner Collaboration Grant from PanKind, The Australian Pancreatic Cancer Foundation in collaboration with Tour de Cure and Woolworths Limited through Woolies on Wheels and Walks. A.R.P. is an NHMRC Peter Doherty Early Career Fellow (1166447). M.P. is supported by an NHMRC career development fellowship (1162556) and NHMRC project grant (1162860). We acknowledge The Collie Foundation for providing funds to purchase the Leica Aperio slide scanner. We also acknowledge the use of the services and facilities of the AGRF.

History

Publication Date

2022-10-11

Journal

Cell Reports

Volume

41

Issue

2

Article Number

111479

Pagination

17p.

Publisher

Elsevier

ISSN

2211-1247

Rights Statement

© 2022 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.