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

Autor:	Allegrezza MJ; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Rutkowski MR; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Stephen TL; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Svoronos N; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Perales-Puchalt A; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Nguyen JM; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Payne KK; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania., Singhal S; Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania., Eruslanov EB; Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania., Tchou J; Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania., Conejo-Garcia JR; Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania. jrconejo@wistar.org.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2016 Nov 01; Vol. 76 (21), pp. 6253-6265.
DOI:	10.1158/0008-5472.CAN-16-1308
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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