Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T ‐cell receptor CD 3‐ ζ chain down‐regulation via caspase‐3 activation in oral cancer

Decreased expression of CD 3‐ 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 CD 3‐ 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 CD 3‐ ζ chain expression. 2′5′‐Oligoadenylate synthetase 2 ( OAS 2) was identified by the proteomic approach and our results established a causative link between CD 3‐ ζ chain down‐regulation and OAS 2 stimulation. The surrogate situation was established by over‐expressing OAS 2 in a HEK 293 cell line and cell‐free supernatant was collected. These supernatants when incubated with T cells resulted in down‐regulation of CD 3‐ ζ chain, which shows that the secreted OAS 2 is capable of regulating CD 3‐ ζ chain expression. Incubation of T cells with cell‐free supernatants of oral tumours or recombinant human OAS 2 (rh‐ OAS 2) induced caspase‐3 activation, which resulted in CD 3‐ ζ chain down‐regulation. Caspase‐3 inhibition/down‐regulation using pharmacological inhibitor or small interfering RNA restored down‐regulated CD 3‐ ζ chain expression in T cells induced by cell‐free tumour supernatant or rh‐ OAS 2. Collectively these results show that OAS 2 leads to impairment in CD 3‐ ζ chain expression, so offering an explanation that might be applicable to the CD 3‐ ζ chain deficiency observed in cancer and diverse disease conditions.