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Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity.

TitleMixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity.
Publication TypeJournal Article
Year of Publication2020
AuthorsKumar S, Singh SKumar, Viswakarma N, Sondarva G, Nair RSathish, Sethupathi P, Sinha SC, Emmadi R, Hoskins K, Danciu O, Thatcher GRJ, Rana B, Rana A
JournalProc Natl Acad Sci U S A
Volume117
Issue14
Pagination7961-7970
Date Published2020 04 07
ISSN1091-6490
KeywordsAnimals, Breast Neoplasms, Cell Line, Tumor, Cyclophilin A, Female, Humans, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Mammary Neoplasms, Experimental, MAP Kinase Kinase Kinases, Mice, NFATC Transcription Factors, Phosphorylation, Primary Cell Culture, Protein Kinase Inhibitors, Pyridines, Pyrroles, T-Lymphocytes, Cytotoxic, Tumor Escape
Abstract

Mixed lineage kinase 3 (MLK3), also known as MAP3K11, was initially identified in a megakaryocytic cell line and is an emerging therapeutic target in cancer, yet its role in immune cells is not known. Here, we report that loss or pharmacological inhibition of MLK3 promotes activation and cytotoxicity of T cells. MLK3 is abundantly expressed in T cells, and its loss alters serum chemokines, cytokines, and CD28 protein expression on T cells and its subsets. MLK3 loss or pharmacological inhibition induces activation of T cells in in vitro, ex vivo, and in vivo conditions, irrespective of T cell activating agents. Conversely, overexpression of MLK3 decreases T cell activation. Mechanistically, loss or inhibition of MLK3 down-regulates expression of a prolyl-isomerase, Ppia, which is directly phosphorylated by MLK3 to increase its isomerase activity. Moreover, MLK3 also phosphorylates nuclear factor of activated T cells 1 (NFATc1) and regulates its nuclear translocation via interaction with Ppia, and this regulates T cell effector function. In an immune-competent mouse model of breast cancer, MLK3 inhibitor increases Granzyme B-positive CD8 T cells and decreases MLK3 and Ppia gene expression in tumor-infiltrating T cells. Likewise, the MLK3 inhibitor in pan T cells, isolated from breast cancer patients, also increases cytotoxic CD8 T cells. These results collectively demonstrate that MLK3 plays an important role in T cell biology, and targeting MLK3 could serve as a potential therapeutic intervention via increasing T cell cytotoxicity in cancer.

DOI10.1073/pnas.1921325117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID32209667
PubMed Central IDPMC7149389
Grant ListIK6 BX004855 / BX / BLRD VA / United States
R01 CA178063 / CA / NCI NIH HHS / United States
R01 CA216410 / CA / NCI NIH HHS / United States
R03 CA219764 / CA / NCI NIH HHS / United States
I01 BX002703 / BX / BLRD VA / United States
I01 BX003296 / BX / BLRD VA / United States
R01 CA176846 / CA / NCI NIH HHS / United States