We have recently observed that there is an infiltration of NKR- P1plus___lymphocytes into established 9L rat gliosarcomas; that sorted populations of NKR-P1plus cells from established 9L tumors have demonstrable but reduced non-MHC restricted cytotoxic activity; and, that following culture in lL2, sorted populations of NKR-P1plus, 9L-infiltrating cells can be induced to mediate lysis of 9L cells in vitro. Among the lymphoid cells infiltrating the tumor, NKR-P1plus cells account for 30-60% of the total population. In contrast, NKR-P1plus cells among PBL and splenocytes represent only about 5-15% of total lymphocytes. Based upon these data and the usual progressive growth and local invasion by the tumor, we hypothesize that there is a selective localization of NKR-P1plus cells in 9L tumors, which are hypofunctional but have the potential to be stimulated/activated to mediate tumor regression. The nature and functional status of lymphocytes infiltrating brain tumors are not well characterized, and an understanding of each will be important for development of effective therapeutic strategies based upon the potential anti-tumor effects of the host~s immune system. Therefore, we propose to use the 9L gliosarcoma as a model to study the selective infiltration and regulation of functional activity of endogenous lymphoid cells in brain tumors.
Our specific aims i nclude: 1. A comparison of the phenotype and function of the lymphocyte population in 9L gliosarcomas and in the periphery. 2. An analysis of the factors regulating lymphoid cell function and localization in 9L gliosarcomas. 3. Testing the hypothesis that effective therapy of 9L gliosarcomas can be accomplished by reversing the immunosuppression of endogeous effector cells in the tumor microevenironment; and/or activting anti-tumor activity of endogenous NKR-P1plus cells by delivery of exogenous cytokines.
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