Several lines of evidence indicate that progressively growing tumor triggers a T cell immune response in the autochthonous host and this immunity can be exploited for therapeutic benefits. Using syngeneic murine tumors, we have previously demonstrated the existence of immunologically sensitized but functionally deficient T lymphocytes in the tumor-draining lymph nodes. These cells, designated as """"""""pre-effector"""""""" cells, could be stimulated in vitro by the tumor cells and IL-2 to differentiate into immune effector cells with demonstrable in vivo antitumor effects. However, the requirement of viable tumor cells for stimulating the pre-effector cells represents a severe deterrence to the clinical application of this procedure. Since specific antigenic recognition by T lymphocytes involves the T cell antigen receptor (TCR)/CD3 complex, we recently developed an alternative procedure for pre-effector cell activation. In the absence of tumor cells, pre-effector cells can differentiate into effector cells upon stimulation with anti-CD3 followed by culture in IL-2. Although the mode of anti-CD3/IL-2 activation is not immunologically specific, cells generated mediate tumor-specific reactivity which is apparently determined during the pre-effector cell sensitized in vivo. The ability to elicit a pre-effector cell response is a general phenomenon and demonstrated in many immunogenic as well as poorly immunogenic tumors. However, eliciting the pre-effector cell response to poorly immunogenic tumors requires the use of the bacterial adjuvant Corynebacterium parvum. In addition, the generation of pre-effector cells in vivo is subjected to down-regulation by the progressive tumor growth and by the presence of visceral metastases. Such suppression is mediated by the tumor-induced suppressor cells and is also immunologically specific. Because the mode of activation by the anti-CD3/IL-2 involves the TCR/CD complex and because both the pre-effector and suppressor cell responses are immunologically specific, the goal of the proposed studies is to elucidate the mechanisms of T cell immune recognition of tumor-associated antigens and to develop methodologies for enhancing the pre-effector cell response for generating and utilizing specific T cell immunity in cancer therapy.
The specific aims are: (1) to identify and selectively activate pre-effector cells according to their usage of TCR V-beta segments; (2) to analyze lymphokine profiles of antitumor effector cells that correlate with in vivo antitumor functions at the clonal level; (3) to determine the heterogeneity of tumor-associated antigens recognized by the anti- CD3/IL-2 activated immune cells; (4) to characterize tumor-specific suppressor cells and their regulatory effects on the pre-effector cell sensitization; and (5) to develop therapeutic manipulations that could result in augmentation of the pre-effector cell sensitization.
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