title: Extracellular 2'5'-oligoadenylate synthetase 2 mediates T-cell receptor CD3-ζ chain down-regulation via caspase-3 activation in oral cancer.
abstract: Decreased expression of CD3-ζ chain, an adaptor protein associated with T-cell signalling, is well documented in patients with oral cancer, but the mechanistic justifications are fragmentary. Previous studies in patients with oral cancer have shown that decreased expression of CD3-ζ chain was associated with decreased responsiveness of T cells. Tumours are known to induce localized as well as systemic immune suppression. This study provides evidence that oral tumour-derived factors promote immune suppression by down-regulating CD3-ζ chain expression. 2'5'-Oligoadenylate synthetase 2 (OAS2) was identified by the proteomic approach and our results established a causative link between CD3-ζ chain down-regulation and OAS2 stimulation. The surrogate situation was established by over-expressing OAS2 in a HEK293 cell line and cell-free supernatant was collected. These supernatants when incubated with T cells resulted in down-regulation of CD3-ζ chain, which shows that the secreted OAS2 is capable of regulating CD3-ζ chain expression. Incubation of T cells with cell-free supernatants of oral tumours or recombinant human OAS2 (rh-OAS2) induced caspase-3 activation, which resulted in CD3-ζ chain down-regulation. Caspase-3 inhibition/down-regulation using pharmacological inhibitor or small interfering RNA restored down-regulated CD3-ζ chain expression in T cells induced by cell-free tumour supernatant or rh-OAS2. Collectively these results show that OAS2 leads to impairment in CD3-ζ chain expression, so offering an explanation that might be applicable to the CD3-ζ chain deficiency observed in cancer and diverse disease conditions.
authors.affiliation: Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Asif A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Trupti N
authors.initials: TN
authors.lastname: Pradhan
authors.affiliation: Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Dakshayni P
authors.initials: DP
authors.lastname: Kulkarni
authors.affiliation: Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Sagar U
authors.initials: SU
authors.lastname: Shah
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Kanury V
authors.initials: KV
authors.lastname: Rao
authors.affiliation: Tata Memorial Hospital, Mumbai, India.
authors.forename: Devendra A
authors.initials: DA
authors.lastname: Chaukar
authors.affiliation: Tata Memorial Hospital, Mumbai, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: D'Cruz
authors.affiliation: Chiplunkar Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Shubhada V
authors.initials: SV
authors.lastname: Chiplunkar
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000201:enzymology* / Q000276:immunology; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019899:Paracrine Communication; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D011994:Recombinant Proteins; C000607948:OAS2 protein, human; D015088:2',5'-Oligoadenylate Synthetase; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: CD3-ζ chain; T cells; humans; tumour immunology; tumour-secreted factors