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Cancer Res. 2014 Jan 1;74(1):153-161. doi: 10.1158/0008-5472.CAN-13-1816. Epub 2013 Nov 18.

Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy.

Mok S#1, Koya RC#2, Tsui C3, Xu J1, Robert L4, Wu L1,3,5,6, Graeber T1,7,3,8, West BL2, Bollag G2, Ribas A1,7,9,3,4.

Author information

1
Department of Molecular and Medical Pharmacology, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (UCLA).
2
Plexxikon Inc., Berkeley, California 94710, U.S.A; Roswell Park Cancer Institute, Buffalo, New York 14263.
3
Institute for Molecular Medicine, UCLA.
4
Department of Medicine, Division of Hematology/Oncology, UCLA.
5
Department of Urology, UCLA.
6
Department of Pediatrics, UCLA.
7
the Jonsson Comprehensive Cancer Center (JCCC) at UCLA.
8
Crump Institute for Molecular Imaging, UCLA.
9
Surgery, Division of Surgical Oncology, UCLA.
#
Contributed equally

Abstract

Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAF(V600E)-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII(low) to MHCII(hi) macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages.

PMID:
24247719
PMCID:
PMC3947337
DOI:
10.1158/0008-5472.CAN-13-1816
[Indexed for MEDLINE]
Free PMC Article

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