OX40 regulatory T cells in cutaneous squamous cell carcinoma suppress effector T cell responses and associate with metastatic potential
| Autor: | Ruth R. French, J. Theaker, Aymen Al-Shamkhani, Amanda S. MacLeod, Ramnik Behar, Martin J. Glennie, Eugene Healy, Suzannah August, Chester Lai, Amel Albibas, Marta E Polak, Shin-Young Cho |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Skin Neoplasms T cell Population Biology Lymphocyte Activation T-Lymphocytes Regulatory Article Immunophenotyping Metastasis Flow cytometry Immunomodulation 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine T-Lymphocyte Subsets medicine Carcinoma Humans Lymphocyte Count Neoplasm Metastasis education education.field_of_study medicine.diagnostic_test Cancer FOXP3 Receptors OX40 medicine.disease Immunohistochemistry Phenotype 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology Carcinoma Squamous Cell Immunologic Memory Biomarkers |
| Popis: | Purpose: 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. Experimental Design: 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. |
| Databáze: | OpenAIRE |
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