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

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Article number111479
Number of pages17
JournalCell Reports
Volume41
Issue number2
DOIs
Publication statusPublished - 11 Oct 2022
Externally publishedYes

Keywords

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

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