Trametinib Drives T-cell–Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis

Abstract

Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of K-Ras-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8+ T cells, which was paradoxical given the drug’s reported ability to inhibit effector lymphocytes. Confirming our observations, adoptive transfer of tumor-derived mMDSC reversed the ability of trametinib to control tumor growth. Overall, our work showed how the effects of trametinib on immune cells could partly explain its effectiveness, distinct from its activity on tumor cells themselves. More broadly, by providing a more incisive view into how MEK inhibitors may act against tumors, our findings expand their potential uses to generally block monocytic MDSC expansion which occurs widely in cancers to drive their growth and progression.

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].…”

BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways

“…For example, it has been proposed that cell death induced by anti-cancer therapy can release tumor antigen, leading to increased T cell functions 21,56 Indeed, it has been shown that MEK inhibition modulates the tumor microenvironment through mechanisms such as pathological myelopoiesis. 57 The effects of MEK inhibitor on T cell functions are also related to tested parameters of T cell functions. We found that MEK inhibitor does not alter expression of Granzyme B in T cells, whereas it inhibits all other tested parameters of T cell functions in this study.…”

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

“…In fact, in a KRAS-inducible breast cancer model, MEK inhibition prevented tumor progression in vivo through an immune-mediated mechanism, rather than by direct inhibition of tumor-cell proliferation. This mechanism, which required CD8 T cells, was mediated by the blockade of monocytic myeloid-derived suppressive cell (mMDSC) expansion [110]. Moreover, MEK inhibition increases the number of CD4 TILs and did not negatively affect the density of CD8 TILs in a fully competent colon carcinoma syngeneic mouse model [111].…”