Megan O'Brien

Ashleigh R. Poh

David Chisanga

Hong He

David Baloyan

Jasmin Traichel

Christine Dijkstra

Michaël Chopin

Stephen L. Nutt

Lachlan Whitehead

Louis Boon

Ashleigh Parkin

Clifford A. Lowell

Marina Pajic

Wei. Q. Shi

Mehrdad Nikfarjam

Matthias Ernst

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

Inhibition of HCK in Myeloid Cells Restricts Pancreatic Tumor Growth and Metastasis

Lachlan Whitehead

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