title: Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells.
abstract: Accumulating evidence suggests elements within tumors induce exhaustion of effector T cells and infiltration of immunosuppressive regulatory T cells (Tregs), thus preventing the development of durable antitumor immunity. Therefore, the discovery of agents that simultaneously block Treg suppressive function and reinvigorate effector function of lymphocytes is key to the development of effective cancer immunotherapy. Previous studies have shown that TLR ligands (TLRLs) could modulate the function of these T cell targets; however, those studies relied on cell-free or accessory cell-based assay systems that do not accurately reflect in vivo responses. In contrast, we used a human PBMC-based proliferation assay system to simultaneously monitor the effect of TLRLs on T cells (CD4(+), CD8(+), Tregs), B cells, and NK cells, which gave different and even conflicting results. We found that the TLR7/8L:CL097 could simultaneously activate CD8(+) T cells, B cells, and NK cells plus block Treg suppression of T cells and B cells. The TLRLs TLR1/2L:Pam3CSK4, TLR5L:flagellin, TLR4L:LPS, and TLR8/7L:CL075 also blocked Treg suppression of CD4(+) or CD8(+) T cell proliferation, but not B cell proliferation. Besides CL097, TLR2L:PGN, CL075, and TLR9L:CpG-A, CpG-B, and CpG-C) were strong activators of NK cells. Importantly, we found that Pam3CSK4 could: 1) activate CD4(+) T cell proliferation, 2) inhibit the expansion of IL-10(+) naturally occurring FOXP3(+) Tregs and induction of IL-10(+) CD4(+) Tregs (IL-10-producing type 1 Treg), and 3) block naturally occurring FOXP3(+) Tregs suppressive function. Our results suggest these agents could serve as adjuvants to enhance the efficacy of current immunotherapeutic strategies in cancer patients.
authors.affiliation: Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; ksvoo@mdanderson.org liuyo@Medimmune.com.
authors.forename: Kui Shin
authors.initials: KS
authors.lastname: Voo
authors.affiliation: Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Laura
authors.initials: L
authors.lastname: Bover
authors.affiliation: Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Megan Lundell
authors.initials: ML
authors.lastname: Harline
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; and.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Weng
authors.affiliation: MedImmune, Gaithersburg, MD 20878.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: MedImmune, Gaithersburg, MD 20878 ksvoo@mdanderson.org liuyo@Medimmune.com.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005408:Flagellin / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D011804:Quinolines / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C551788:CL 075; C547051:CL097 compound; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D015850:Interleukin-6; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D011804:Quinolines; D013844:Thiazoles; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; D016753:Interleukin-10; D007371:Interferon-gamma