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

2022-10-11

Poh, Ashleigh R

O'Brien, Megan

Chisanga, David

He, Hong

Baloyan, David

Traichel, Jasmin

Dijkstra, Christine

Chopin, Michaël

Nutt, Stephen

Whitehead, Lachlan

Boon, Louis

Parkin, Ashleigh

Lowell, Clifford

Pajic, Marina

Shi, Wei

Nikfarjam, Mehrdad

Ernst, Matthias

CP: Cancer

CP: Immunology

desmoplasia

drug resistance

hematopoietic cell kinase

immune suppression

immunotherapy

myeloid cells

pancreatic cancer

tumor microenvironment

Journal Article

10.1016/j.celrep.2022.111479

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.

link

Cell Reports 2022; 41(2): 111479

Cell Reports