Volume 1 Supplement 1
MAP kinase inhibitors stimulate T cell and anti-tumor activity in combination with blockade of the PD-L1/PD-1 interaction
© Irving et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Pharmacological inhibition of the MAPK pathway with MEK or BRAF antagonists has proved successful in inducing regression of melanoma tumors bearing the targeted activating mutations. Moreover, antibodies targeting T-cell immune checkpoint inhibitors CTLA-4 or PD-L1/PD-1 have demonstrated the capacity to generate durable responses in patients with multiple cancer types. Thus, combining MAPK pathway-targeted agents with antibodies that enhance anti-tumor immunity represents an increasingly attractive treatment paradigm for cancer. However, little is known about the impact of tumor-targeted agents on immune function as similar signaling pathways drive both T-cell activation and cancer cell proliferation. Accordingly, agents targeting MAPK-dependent tumor growth would be predicted to also inhibit T-cell immunity. Here we show that, unexpectedly, potent suppression of T-cell receptor (TCR) function by MEK inhibition can be largely overcome in the presence of co-stimulation by anti-CD28 in vitro or blockade of the inhibitory PD-L1/PD-1 pathway in T cells in vivo. The ability of anti-CD28 to override suppression of T-cell activation by MEK inhibitors was dependent on the PI3K/mTOR pathway. Enhanced anti-tumor activity was also observed combining MEK inhibition with PD-L1 blockade, which was likely potentiated by upregulation of tumor MHC Class I expression through inhibition of MEK. Interestingly, inhibitors targeting BRAF V600E mutations actually augmented TCR-driven proliferation in vitro and T-cell function in vivo when combined with a vaccine or blockade of PD-L1 exclusively in the context of a wildtype BRAF background. These data demonstrate that targeting the MAPK pathway can be compatible with or even enhance T-cell function and provide rationale for combining these inhibitors with immunotherapy in clinical trials.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.