Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.

Détails

ID Serval
serval:BIB_F7875BCF67D2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFNγ.
Périodique
Cancer research
Auteur(s)
Ho P.C., Meeth K.M., Tsui Y.C., Srivastava B., Bosenberg M.W., Kaech S.M.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Statut éditorial
Publié
Date de publication
15/06/2014
Peer-reviewed
Oui
Volume
74
Numéro
12
Pages
3205-3217
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Résumé
B-Raf(V600E) inhibitors have been suggested to promote tumor regression with the help of host immunity, but this hypothesis has not been examined directly in detail. In this study, we profiled immunologic changes in the tumor microenvironment and tumor-infiltrating lymphocytes (TIL) in a B-RafV600E/Pten-driven murine model of melanoma after administration of the B-Raf(V600E) small molecule inhibitor PLX4720. In this model, we found that as tumors developed, they gradually acquired immunosuppressive features, including accumulation of regulatory T cells (Treg) and CD11b(+)/Gr-1(+) myeloid cells and loss of Th1 effector functions on CD4(+) TILs, such as CD40L and IFNγ expression. PLX4720 administration promoted development of a more immune stimulatory microenvironment associated with a relative increase in CD40L and IFNγ expression on intratumoral CD4(+) TILs and a reduced accumulation of Tregs and CD11b(+)/Gr-1(+) myeloid cells. Strikingly, CD40L or IFNγ blockade compromised the ability of PLX4720 to inhibit melanoma growth. Supporting this result, agonistic CD40 antibody was sufficient to evoke antitumor immunity and suppress tumor growth in tumor-bearing mice. Taken together, our results establish the critical role of immune-related changes, with key contributions for CD40L and IFNγ signaling in the antitumor responses triggered in vivo by B-Raf(V600E) inhibitors.
Mots-clé
Animals, Antigen-Presenting Cells/drug effects, Antigen-Presenting Cells/immunology, Antineoplastic Agents/pharmacology, CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/immunology, CD40 Ligand/physiology, Drug Screening Assays, Antitumor, Indoles/pharmacology, Interferon-gamma/physiology, Macrophages/drug effects, Macrophages/immunology, Melanoma, Experimental/drug therapy, Melanoma, Experimental/immunology, Melanoma, Experimental/metabolism, Mice, Mice, Transgenic, Mutation, Missense, Proto-Oncogene Proteins B-raf/antagonists & inhibitors, Proto-Oncogene Proteins B-raf/genetics, Proto-Oncogene Proteins B-raf/metabolism, Signal Transduction, Skin Neoplasms/drug therapy, Skin Neoplasms/immunology, Skin Neoplasms/metabolism, Sulfonamides/pharmacology, Tumor Microenvironment/immunology
Pubmed
Web of science
Open Access
Oui
Création de la notice
05/04/2019 16:25
Dernière modification de la notice
20/08/2019 17:23
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