title: Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation.
abstract: Intratumoral immune activation can induce local and systemic antitumor immunity. Imiquimod is a cream-formulated, TLR7 agonist that is Food and Drug Administration approved for the treatment of nonmelanoma skin cancers, but it has limited activity against melanoma. We studied the antitumor activity and mechanism of action of a novel, injectable, tissue-retained TLR7/8 agonist, 3M-052, which avoids systemic distribution. Intratumoral administration of 3M-052 generated systemic antitumor immunity and suppressed both injected and distant, uninjected wild-type B16.F10 melanomas. Treated tumors showed that an increased level of CCL2 chemokines and infiltration of M1 phenotype-shifted macrophages, which could kill tumor cells directly through production of NO and CCL2, were essential for the antitumor activity of 3M-052. CD8(+) T cells, B cells, type I IFN, IFN-γ, and plasmacytoid dendritic cells were contributed to efficient tumor suppression, whereas perforin, NK cells, and CD4 T cells were not required. Finally, 3M-052 therapy potentiated checkpoint blockade therapy with anti-CTLA-4 and anti-programmed death ligand 1 Abs, even when checkpoint blockade alone was ineffective. Our findings suggest that intratumoral treatment with 3M-052 is a promising approach for the treatment of cancer and establish a rational strategy and mechanistic understanding for combination therapy with intratumoral, tissue-retained TLR7/8 agonist and checkpoint blockade in metastatic cancer.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Manisha
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
authors.forename: Hiep
authors.initials: H
authors.lastname: Khong
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Xue-Fei
authors.initials: XF
authors.lastname: Huang
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: 3M Drug Delivery Systems Division, 3M Company, St. Paul, MN 55144.
authors.forename: John P
authors.initials: JP
authors.lastname: Vasilakos
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030;
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030; WOverwijk@mdanderson.org.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D015552:Injections, Intralesional; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D018932:Chemokine CCL2; D007093:Imidazoles; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D009569:Nitric Oxide; C402365:resiquimod