Immunosuppression appears to be more frequent and more profound in patients with head and neck cancer. The immune impairment often observed in these patients is not restricted to the tumor site but presents itself as a systemic defect. The project aims at understanding the molecular mechanism of CD3 ζ chain degradation, both at the mRNA and protein level. Studies demonstrate a marked reduction in lymphocyte proliferative responses, calcium flux and a strong TH2 bias in OC patients.
The present project aims at understanding the role of Toll like receptors (TLRs) and regulatory T cells in modulating the anti tumor immunity mediated by γδ T cells in patients with oral and cervical cancer. Preliminary work demonstrated the presence of TLRs (TLR2, TLR3, TLR4 and TLR9) on γδ T cells from freshly isolated peripheral blood leucocytes (PBLs). γδ T cells were immunomagnetically purified from ex-vivo expanded PBLs and stimulated in the presence of a TCR stimulus (IPP and anti-CD3) or a TLR stimulus (Poly I:C) or both in combination.
We are currently interested in analyzing the non-peptidic ligands recognized by γδ T cells on tumor cells. Our studies demonstrate that T lymphocytes expressing the Vγ9/Vδ2 TCR recognize non-peptidic phosphorylated compounds, their synthetic analogs bisphosphonates and endogenous metabolite Isopentenyl pyrophosphate (intermediate metabolite of mevalonate pathway) in tumor cells. γδ T cells release IFN-gamma and TNF-alpha after co-culture with a panel of oral, breast and prostate tumor cell lines as against lowered cytokines in normal, non-transformed cell lines.
γδ T cells play an important role as anti-tumor effector cells. However, their expansion is self-limiting. We investigated the activation induced cell death in γδ T cells after stimulation with heat shock proteins (hsp60, hsp70) that act as ligands for γδ T cells. Characterization of the molecular events in the apoptotic pathway revealed that nitric oxide (NO) is released by γδ T cells after hsp stimulation. Purified γδ T cells when incubated with rhsp60 and rhsp70 as well as artificial NO donors - SNAP and arginine, exhibited changes in mitochondrial membrane potential.
