ORAL CARCINOMA--SIGNAL TRANSDUCTION IN LYMPHOCYTES

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Progressive growth of oral cavity squamous cell carcinoma of (OSCC) is associated with deleterious effects on the immune response. We have demonstrated that tumor-infiltrating lymphocytes (TIL), tumor involved lymph node T lymphocytes and, in advanced disease, also peripheral blood T lymphocytes from cancer patients are partially deficient in the ability to transmit stimulatory signals to the interior of the cell. These impairments are related to alterations in expression or function of signal transducing molecules TcR zeta-chain and p56 lck. Success of gene-or immunotherapy approaches depends on reversal of TcR/CD3 signaling defects and restoration of immune responsiveness. Several studies have suggested that defective T cells from tumor-bearing hosts were not irreversibly damaged. Our observations in cancer patients undergoing biologic therapies indicate that recovery in expression TcR zeta-chain correlates with response to therapy. The goal of this proposal is to define the molecular basis and mechanisms responsible for the immune hyporesponsiveness in OSCC patients, and determine whether these defects can be reversed by biologic therapies. We propose to characterize the alterations in the TcR/CD3 signaling pathway in lymphocytes from patient with OSCC and the relationship between these alterations and the disease stage, prognosis and response to therapy. The biologic therapies to be evaluated are:(i) locoregional therapy with autologous fibroblasts transduced with the IL-12 gene and producing biologically active IL-12 (Project 3); (ii) systemic therapy with IL-12 protein (Project 3); and (iii) local therapy with the wild-type p53 tumor suppressor gene, which will be introduced in later years into OSCC tumors expressing mutant p53 (Project 2). Additional therapies with OSCC peptides and DC (Project 1 and 3) will be introduced in later years. We also propose to investigate potential mechanisms responsible for the reduced level of expression of zeta-chain in T lymphocytes from OSCC patients. The proposed experimental strategy is supported by our observations that fresh tumor cells induce a partial loss in expression of zeta-chain in autologous PL-T lymphocytes during in vitro co-incubation. This reduction in zeta-chain expression appears to be related to tumor-induced endogenous proteolytic process in lymphocytes, since pretreatment of autologous T-lymphocytes with LLnL, a potent protease inhibitor, blocked the degradation of zeta-chain. We, therefore, hypothesize that an endogenous proteolytic process is responsible for the zeta-chain deficiency in T lymphocytes from patients with OSCC.