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

Poh, AR; O&#39;Brien, M; Chisanga, D; He, H; Baloyan, D; Traichel, J; Dijkstra, C; Chopin, M; Nutt, S; Whitehead, L; Boon, L; Parkin, A; Lowell, C; Pajic, M; Shi, W; Nikfarjam, M; Ernst, M

Author(s): Poh, AR; O'Brien, M; Chisanga, D; He, H; Baloyan, D; Traichel, J; Dijkstra, C; Chopin, M; Nutt, S; Whitehead, L; Boon, L; Parkin, A; Lowell, C; Pajic, M; Shi, W; Nikfarjam, M; Ernst, M;
Details: Publication Year 2022-10-11,Volume 41,Issue #2,Page 111479
Journal Title: Cell Reports
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.
Publisher: Cell Press
Keywords: CP: Cancer; CP: Immunology; desmoplasia; drug resistance; hematopoietic cell kinase; immune suppression; immunotherapy; myeloid cells; pancreatic cancer; tumor microenvironment
Research Division(s): Immunology; Advanced Technology And Biology
PubMed ID: 36223746
Publisher's Version: https://doi.org/10.1016/j.celrep.2022.111479
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2022.111479
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Poh AR et al_Cancer Reports_2022.pdf - (3.95MB, application/pdf)

Creation Date: 2022-10-14 09:03:10

Last Modified: 2022-10-14 09:08:26