MEK inhibition suppresses B regulatory cells and augments anti-tumor immunity
| Autor: | Aditya Mohan, Mark Yarchoan, Elizabeth M. Jaffee, Nilofer S. Azad, Amanda Ruggieri, Gregory B. Lesinski, Teena Vithayathil, Todd D. Armstrong, Lauren Dennison |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Cell signaling B Cells medicine.medical_treatment Cancer Treatment Signal transduction White Blood Cells Mice 0302 clinical medicine Piperidines Cancer immunotherapy Animal Cells Medicine and Health Sciences Cytotoxic T cell Extracellular Signal-Regulated MAP Kinases Immune Response B-Lymphocytes Regulatory Mice Inbred BALB C Multidisciplinary T Cells Chemistry MEK inhibitor Signaling cascades 3. Good health medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Colonic Neoplasms Medicine Immunotherapy Cellular Types Anatomy Colorectal Neoplasms Research Article Proto-Oncogene Proteins B-raf MAPK signaling cascades Science Immune Cells Immunology Cytotoxic T cells Cancer Immunotherapy Lymphatic System 03 medical and health sciences Immune system Cell Line Tumor medicine Animals Humans Antibody-Producing Cells Protein Kinase Inhibitors B cell Mitogen-Activated Protein Kinase Kinases Blood Cells Biology and Life Sciences Cell Biology Xenograft Model Antitumor Assays Genes ras 030104 developmental biology Humoral immunity Cancer research Azetidines Clinical Immunology Lymph Nodes Clinical Medicine |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 10, p e0224600 (2019) |
| ISSN: | 1932-6203 |
| Popis: | Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS pathway and a therapeutic target in RAS-driven cancers. Although tumor responses to MEK inhibition are rarely durable, MEK inhibitors have shown substantial activity and durable tumor regressions when combined with systemic immunotherapies in preclinical models of RAS-driven tumors. MEK inhibitors have been shown to potentiate anti-tumor T cell immunity, but little is known about the effects of MEK inhibition on other immune subsets, including B cells. We show here that treatment with a MEK inhibitor reduces B regulatory cells (Bregs) in vitro, and reduces the number of Bregs in tumor draining lymph nodes in a colorectal cancer model in vivo. MEK inhibition does not impede anti-tumor humoral immunity, and B cells contribute meaningfully to anti-tumor immunity in the context of MEK inhibitor therapy. Treatment with a MEK inhibitor is associated with improved T cell infiltration and an enhanced response to anti-PD1 immunotherapy. Together these data indicate that MEK inhibition may reduce Bregs while sparing anti-tumor B cell function, resulting in enhanced anti-tumor immunity. |
| Databáze: | OpenAIRE |
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