Abstract
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.
Highlights
The mitogen-activated protein kinase (MAPK) cascade is a critical pathway for cell proliferation and inhibition of apoptosis and is one of the most frequently dysregulated driver pathways in cancer [1]
Mitogen/Extracellular signal regulated Kinase (MEK) inhibition reprograms B cells in Vitro in the setting of B cell antigen receptor (BCR) engagement To identify a potential relationship between MAPK pathway inhibition and B cell mediated immune responses, we first assessed the effect of the highly specific MEK inhibitor GDC-0973[15] on isolated splenic B cells in vitro
Because the MAPK pathway partially mediates B cell responses to antigen stimulation [14], we further investigated the effects of MEK inhibition in the setting of BCR engagement
Summary
The mitogen-activated protein kinase (MAPK) cascade is a critical pathway for cell proliferation and inhibition of apoptosis and is one of the most frequently dysregulated driver pathways in cancer [1]. Aberrant activation of the MAPK pathway resulting from activating mutations in RAS or RAF is observed in a wide number of human cancers including many melanomas, non-small cell lung cancers, colorectal cancers, and other tumor types. MEK itself is rarely mutated in human cancers, it is a downstream effector of mutant alleles of Rapidly Accelerated Fibrosarcoma (RAF) or RAS and mediates constitutive activation of the MAPK pathway [2]. Due to the emergence of drug resistant clones, tumor responses to targeted inhibition of the MAPK pathway are rarely durable
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