title: Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors.
abstract: Acquired resistance to BRAFV600Einhibitors (BRAFi) in melanoma remains a common clinical obstacle, as is the case for any targeted drug therapy that can be developed given the plastic nature of cancers. Although there has been significant focus on the cancer cell-intrinsic properties of BRAFi resistance, the impact of BRAFi resistance on host immunity has not been explored. Here we provide preclinical evidence that resistance to BRAFi in an autochthonous mouse model of melanoma is associated with restoration of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, initially reduced by BRAFi treatment. In contrast to restoration of MDSCs, levels of T regulatory cells remained reduced in BRAFi-resistant tumors. Accordingly, tumor gene expression signatures specific for myeloid cell chemotaxis and homeostasis reappeared in BRAFi-resistant tumors. Notably, MDSC restoration relied upon MAPK pathway reactivation and downstream production of the myeloid attractant CCL2 in BRAFi-resistant melanoma cells. Strikingly, although combination checkpoint blockade (anti-CTLA-4 + anti-PD-1) was ineffective against BRAFi-resistant melanomas, the addition of MDSC depletion/blockade (anti-Gr-1 + CCR2 antagonist) prevented outgrowth of BRAFi-resistant tumors. Our results illustrate how extrinsic pathways of immunosuppression elaborated by melanoma cells dominate the tumor microenvironment and highlight the need to target extrinsic as well as intrinsic mechanisms of drug resistance.Cancer Res; 77(7); 1599-610. ©2017 AACR.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Tamer B
authors.initials: TB
authors.lastname: Shabaneh
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Peisheng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Malik
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Wood
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Andrea
authors.initials: A
authors.lastname: Boni
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Molodtsov
authors.affiliation: Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Christina V
authors.initials: CV
authors.lastname: Angeles
authors.affiliation: Division of Hematology & Medical Oncology, Cancer Therapy & Research Center, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.|Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Mary.jo.turk@dartmouth.edu.|Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D007211:Indoles; C528407:PLX 4720; D054390:Receptors, CCR2; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf