Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis.
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 KRas-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 mMDSC expansion, which occurs widely in cancers to drive their growth and progression. Cancer Res; 76(21); 6253-65. ©2016 AACR.
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Michael J
MJ
Allegrezza
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Melanie R
MR
Rutkowski
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Tom L
TL
Stephen
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Nikolaos
N
Svoronos
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Alfredo
A
Perales-Puchalt
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Jenny M
JM
Nguyen
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Kyle K
KK
Payne
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Sunil
S
Singhal
Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Evgeniy B
EB
Eruslanov
Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Julia
J
Tchou
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania. jrconejo@wistar.org.
Jose R
JR
Conejo-Garcia
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D022423:Myeloid Cells / Q000187:drug effects / Q000502:physiology; D038042:Myelopoiesis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D053495:Osteopontin / Q000096:biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000502:physiology*
D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011728:Pyridones; D011744:Pyrimidinones; D053495:Osteopontin; C560077:trametinib; D016283:Proto-Oncogene Proteins p21(ras)