Although immune responses directed towards various tumor antigens can be detected in rodent models and cancer patients, these anti-tumor responses are incapable of eliminating cancer in vivo. Three major obstacles appear to be responsible for the poor anti-tumor responses in vivo: First, the inability of tumors to initiate, amplify and maintain CTL responses because they lack costimulatory molecules, thereby inducing T cell anergy instead of priming in tumor infiltrating T lymphocytes. Second, the expression of PD-L1 by tumor cells via which they initiate PD-1mediated negative signals to tumor infiltrating T lymphocytes, leading to their inactivation and potential apoptosis. Third, the production of soluble factors (predominantly TGF-2), by tumor cells via which they inhibit both T cell activation and expansion and presentation of antigens on antigen presenting cells. p27, a member of the Cip/Kip family of cyclin-dependent kinase (cdk) inhibitors, is a critical inhibitor of cell cycle progression. Recently, we observed that p27 deficient T cells are resistant to tolerance induction by blockade of costimulation. Consistently, p27 deficient recipients reject cardiac allografts under conditions that induce long-term allograft survival in wild-type recipients. We have also observed that p27 deficient CTL express lower levels of PD-1 than their wild-type counterparts. Finally, compared to their wild-type + counterparts, p27 deficient CD8 cells are less susceptible to the inhibitory effects of TGF-2. These properties of p27 deficient lymphocytes suggest that elimination of p27 may overcome three major mechanisms via which tumor cells escape immune surveillance in vivo. In this proposal we will explore the possibilities that p27 deficient T cells may be capable of mounting effective anti-tumor responses and may eradicate established tumors. To address these issues we will undertake the following two specific aims to examine: First, whether + p27 deficient CD8 T cells can differentiate into efficient tumor-specific CTL under tolerogenic conditions. Second, whether p27 deficient CTL can efficiently suppress tumor growth. Information obtained from these studies will open a new avenue in immunotherapy against tumor, possibly also against virus infection. Project Narrative Information obtained from these studies will open a new avenue in immunotherapy against tumor, possibly also against virus infection.
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