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

Cell reports 2022 Oct 11

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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. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

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. Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis. Cell reports. 2022 Oct 11;41(2):111479