The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment

Abstract

BackgroundT-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME).MethodsIn mice, the effects of MEK inhibition, via selumetinib, and anti-CTLA-4 on immune responses to keyhole limpet haemocyanin (KLH) immunization were monitored using ex vivo functional assays with splenocytes. In a KRAS-mutant CT26 mouse colorectal cancer model, the impact on the tumor microenvironment (TME) and the spleen were evaluated by flow cytometry. The TME was further examined by gene expression and immunohistochemical analyses. The combination and sequencing of selumetinib and anti-CTLA-4 were also evaluated in efficacy studies using the CT26 mouse syngeneic model.ResultsAnti-CTLA-4 enhanced the generation of KLH specific immunity following KLH immunization in vivo; selumetinib was found to reduce, but did not prevent, this enhancement of immune response by anti-CTLA-4 in vivo. In the CT26 mouse model, anti-CTLA-4 treatment led to higher expression levels of the immunosuppressive mediators, Cox-2 and Arg1 in the TME. Combination of anti-CTLA-4 with selumetinib negated this up-regulation of Cox-2 and Arg1, reduced the frequency of CD11+ Ly6G+ myeloid cells, and led to the accumulation of differentiating monocytes at the Ly6C+ MHC+ intermediate state in the tumor. We also report that MEK inhibition had limited impact on anti-CTLA-4-mediated increases in T-cell infiltration and T-cell activation in CT26 tumors. Finally, we show that pre-treatment, but not concurrent treatment, with selumetinib enhanced the anti-tumor activity of anti-CTLA-4 in the CT26 model.ConclusionThese data provide evidence that MEK inhibition can lead to changes in myeloid cells and immunosuppressive factors in the tumor, thus potentially conditioning the TME to facilitate improved response to anti-CTLA-4 treatment. In summary, the use of MEK inhibitors to alter the TME as an approach to enhance the activities of immune checkpoint inhibitors warrants further investigation in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-017-0268-8) contains supplementary material, which is available to authorized users.

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

“…Consistently, in colon carcinoma syngeneic mouse models, the combination of MEK inhibition with either anti-PD-1 [111,112], anti-PD-L1 [111], or anti-CTLA4 [106,111] results in a synergistic effect. In a subsequent study on TN mouse models, the investigators showed that MEK inhibition can have a detrimental effect on T-cell homing, proliferation, and effector functions [115].…”

“…Continued monocyte to tumor-associated macrophage (TAM) differentiation, substantiated by the increase in the intratumoral frequency of intermediary differentiated monocytes expressing MHC II, and the decrease in intratumoral granulocytic myeloid-derived suppressive cells (gMDSCs) [106]. Conversely, because of the critical role of the ERK-MAPK pathway in T-cell function, MEK inhibition can theoretically dampen T-cell antitumor activity.…”

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…In this case, PD-L1 increased expression was associated with immune evasion, indicating that KRAS mutant cancers could indeed benefit from treatment with anti-PD-L1 or anti-PD-1 immune checkpoint inhibitors. Interestingly, some works have already demonstrated that despite the lack of clinical relevance of MEK inhibitors when used as single agents, their combination with immunotherapies can result in increased clinical benefit [49][50][51][52]. These works claimed an effect of MEK inhibitors on the modulation of the immune-suppressive microenvironment that synergized with anti-PD-L1 or anti-CTLA-4 therapies to enhance treatment response [49,52].…”

The pioneers behind immune checkpoint blockers awarded the Nobel Prize in physiology or medicine 2018

“…Combinations of ICB therapy with targeted drugs [119][120][121], chemotherapy [122,123] and radiation [124,125] are currently in clinical trials. It is important that CD8 T-cells may attack cancer cells in any site in the body, thus being a systemic anticancer agent.…”