title: OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential.
abstract: OBJECTIVE
  Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.
  
  
  METHODS
  Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically.
  
  
  RESULTS
  FOXP3(+) Tregs were more frequent in cSCCs than in peripheral blood (P < 0.0001, n = 86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4(+) (P = 0.005, n = 10 tumors) and CD8(+) T cells (P = 0.043, n = 9 tumors) and inhibited IFNγ secretion by tumoral effector T cells (P = 0.0186, n = 11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (P < 0.0001, n = 15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4(+) lymphocyte proliferation (P = 0.0098, n = 10 tumors). Tregs and OX40(+) lymphocytes were more abundant in primary cSCCs that metastasized than in primary cSCCs that had not metastasized (n = 48 and n = 49 tumors, respectively).
  
  
  CONCLUSIONS
  Tregs in cSCCs suppress effector T-cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis. Clin Cancer Res; 22(16); 4236-48. ©2016 AACR.
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Chester
authors.initials: C
authors.lastname: Lai
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Suzannah
authors.initials: S
authors.lastname: August
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Amel
authors.initials: A
authors.lastname: Albibas
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Ramnik
authors.initials: R
authors.lastname: Behar
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Polak
authors.affiliation: Histopathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Theaker
authors.affiliation: Dermatology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: MacLeod
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.affiliation: Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. ehealy@soton.ac.uk.
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
mesh_terms: D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory; D056747:Immunomodulation; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D010641:Phenotype; D053262:Receptors, OX40 / Q000819:agonists / Q000378:metabolism*; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human