title: Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells.
abstract: The immune response to the tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival, and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We show that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and subcutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8(+) T cells within the tumor, reduces the frequency of FoxP3-expressing CD4(+) T cells within tumors, and potentiates the ability of NK1.1(+) and CD8(+) tumor infiltrating cells to secrete IFNγ upon coculture with tumor cells. The enhanced effector function correlated with lower levels of PD-1 expression on CD8(+) T cells from anti-CD27-treated mice. Despite the modulating effect of anti-CD27 on multiple cell types, only CD8(+) T cells were absolutely required for tumor control. The CD4(+) T cells were dispensable, whereas NK1.1(+) cells were needed during early stages of tumor growth but not for the effectiveness of anti-CD27. Thus, CD27-mediated costimulation provides a potent boost to multiple aspects of the endogenous responses to tumor, and may be exploited to enhance tumor immunity.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Roberts
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Franklin
authors.forename: Lara M
authors.initials: LM
authors.lastname: Kingeter
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Alison L
authors.initials: AL
authors.lastname: Tutt
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: Timothy N J
authors.initials: TN
authors.lastname: Bullock
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D047368:Tumor Burden / Q000187:drug effects; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7