TY - JOUR
T1 - MEK inhibition suppresses B regulatory cells and augments anti-tumor immunity
AU - Yarchoan, Mark
AU - Mohan, Aditya A.
AU - Dennison, Lauren
AU - Vithayathil, Teena
AU - Ruggieri, Amanda
AU - Lesinski, Gregory B.
AU - Armstrong, Todd D.
AU - Azad, Nilofer S.
AU - Jaffee, Elizabeth M.
N1 - Funding Information:
National Cancer Institute (NCI) of the National Institutes of Health (NCI) (R01CA228414, to MY, NA, and GL), The Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, The Viragh Foundation, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), and the NIH Center Core Grant (P30CA006973). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Oncology Tissue Services at Johns Hopkins for technical assistance with this manuscript.
Publisher Copyright:
© 2019 Yarchoan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0224600
DO - 10.1371/journal.pone.0224600
M3 - Article
C2 - 31671149
AN - SCOPUS:85074358062
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 10
M1 - e0224600
ER -