title: Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy.
abstract: The ability of immune-based cancer therapies to elicit beneficial CD8(+) CTLs is limited by tolerance pathways that inactivate tumor-specific CD4 Th cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 Th cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8(+) CTL priming as long as the cognate epitopes are linked via presentation on the same dendritic cell. In this study, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that provide help via the above-mentioned classical linked pathway, as well as provide nonlinked help that facilitates CTL function in T cells not directly responding to cognate Ag. We found that engagement of tumor-unrelated CD4 Th cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual costimulated helper cells are themselves helped by a CD134(+) cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B(+) effector CD8 T cells and a reciprocal decrease in Foxp3(+)CD4(+) cell frequency. Notably, the tumor-unrelated CD4 Th cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the antitumor response.
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and.
authors.forename: Payal
authors.identifier: http://orcid.org/0000-0002-5754-3108
authors.initials: P
authors.lastname: Mittal
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and.
authors.forename: Marie-Clare
authors.initials: MC
authors.lastname: St Rose
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and.
authors.forename: Xi
authors.identifier: http://orcid.org/0000-0001-8916-5132
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and.
authors.forename: Joseph M
authors.identifier: http://orcid.org/0000-0002-6333-9533
authors.initials: JM
authors.lastname: Ryan
authors.affiliation: The Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: Jeffrey S
authors.identifier: http://orcid.org/0000-0001-5917-2796
authors.initials: JS
authors.lastname: Wasser
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
authors.affiliation: Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and aadler@uchc.edu.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Adler
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020239:Receptor Cross-Talk; D053262:Receptors, OX40 / Q000378:metabolism*; D012878:Skin Neoplasms / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D053262:Receptors, OX40; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9