title: PD-1 blockage delays murine squamous cell carcinoma development.
abstract: Engagement of programmed death-1 (PD-1) with its two ligands [programmed death ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of tumor-reactive T cells; however, the underlying mechanism for this T-cell dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor regulation by modulation of the tumor environment. In the present study, we used a multistage model of SCC to examine the role of PD-1/PD-L1 activation during tumor development. Tumor sites presented an increased percentage of CD4(+) and CD8(+) T cells expressing PD-1 when compared with non-tumorigenic control mice, whereas the expression of PD-L1 was particularly increased in F4/80(+) macrophages in tumor sites. Further, the systemic immune neutralization of PD-1 resulted in a decreased number and delayed incidence rate of papillomas followed by a differential expression of cytokeratins, suggesting that the PD-1-PD-L1 interaction contributes to the progression of SCC by downregulation of antitumor responses. In fact, blocking PD-1 increased the percentage of CD8(+) and CD4(+) T cells, and the levels of interferon-γ in the tumor sites. Our results indicated involvement of PD-1(+) T cells in SCC development and in the modulation of the inflammatory immune response.
authors.affiliation: Department of Biological Sciences and.
authors.forename: Eduardo Bertoli
authors.initials: EB
authors.lastname: Belai
authors.forename: Carine Ervolino
authors.initials: CE
authors.lastname: de Oliveira
authors.forename: Thaís Helena
authors.initials: TH
authors.lastname: Gasparoto
authors.forename: Rodrigo Nalio
authors.initials: RN
authors.lastname: Ramos
authors.forename: Sergio Aparecido
authors.initials: SA
authors.lastname: Torres
authors.forename: Gustavo Pompermaier
authors.initials: GP
authors.lastname: Garlet
authors.forename: Karen Angélica
authors.initials: KA
authors.lastname: Cavassani
authors.forename: João Santana
authors.initials: JS
authors.lastname: Silva
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Campanelli
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010212:Papilloma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate