title: Depleting tumor-specific Tregs at a single site  eradicates disseminated tumors.
abstract: Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Marabelle
authors.forename: Holbrook
authors.initials: H
authors.lastname: Kohrt
authors.forename: Idit
authors.initials: I
authors.lastname: Sagiv-Barfi
authors.forename: Bahareh
authors.initials: B
authors.lastname: Ajami
authors.forename: Robert C
authors.initials: RC
authors.lastname: Axtell
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.forename: Ranjani
authors.initials: R
authors.lastname: Rajapaksa
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: James
authors.initials: J
authors.lastname: Torchia
authors.forename: Joshua
authors.initials: J
authors.lastname: Brody
authors.forename: Richard
authors.initials: R
authors.lastname: Luong
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rosenblum
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Hyam I
authors.initials: HI
authors.lastname: Levitsky
authors.forename: Victor
authors.initials: V
authors.lastname: Tse
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D056747:Immunomodulation; D007167:Immunotherapy; D015552:Injections, Intralesional; D008212:Lymphocyte Depletion; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008577:Meningeal Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D053262:Receptors, OX40 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists; D047368:Tumor Burden
chemical_list: D000276:Adjuvants, Immunologic; D058846:Antibodies, Monoclonal, Murine-Derived; D060908:CTLA-4 Antigen; C423449:CpG ODN 1826; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides; D053262:Receptors, OX40; C495370:Tlr9 protein, mouse; C505717:Tnfrsf4 protein, mouse; D051217:Toll-Like Receptor 9