Abstract
Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin α4β1 activation, as well as tumor inflammation and progression. These results demonstrate a critical role for myeloid cell MLCK210 in tumor inflammation and serve as basis for the development of alternative approaches to develop immune oncology therapeutics.
Original language | English (US) |
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Article number | 1768 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2022 |
Funding
These studies were supported by NIH grants 5R01CA226909 J.A.V., 5R01CA167426 J.A.V., and 5R01DE027325 J.A.V. This project was partially supported by NCI P30CA23100 to the UCSD Moores Comprehensive Cancer Center for Flow Cytometry Shared Resource services.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy