The goal is to determine the mechanisms involved in the effector phase of the control or rejection of tumor in a versatile experimental model. We will test our hypothesis that the cytokines, chemokines, adhesion and other molecules that are differentially expressed on Tc1 and Tc2 CD8 T cells lead to different mechanisms of tumor control. In our experimental model, we use two tumors, B16ova melanoma and EG7 thymoma, both transfected with ovalbumin to provide a nominal tumor antigen. The B16 is injected iv and grows in the lung with low levels of MHC Class 1 expression; the EG7 is injected id, ip or iv and is localized to the skin, peritoneal cavity or grows systematically. Polarized populations of Tc1 and Tc2 CD8 effector T cells are generated in vitro, from wildtype or various knockout ova-specific TcR transgenic Thy1.2+OT-1 mice and are injected into Th1-1.1+ congenic tumor bearing normal recipients or into syngeneic recipients deficient in various gene functions. Our readouts are survival, rate of tumor growth, fate of the adoptively transferred cells and the determination of the various elements of host cell participating in the ensuing response to the tumor. Ag processing presentation and T cell activation are bypassed in this model and are thus able to focus on the efferent side of the anti-tumor response. Comparison of the results in the various tumor models will allow us to identify components specific in tumor type or to tumor location.
In AIM 1 we will explore the mechanisms whereby adoptively transferred Tc1 and Tc2 CD8 effector T cells prolong the survival of tumor being hosts using effectors from various knockout mice. We will determine the rate of entry of Tc1 and Tc2 cells into the tumor site, spleen and lymph nodes and determine how long they persist, to test the hypothesis that homing and persistence are important requirements for successful therapy.
In AIM 2, we hypothesize that the host plays a significant role in the anti-tumor response following the initial reaction of the transferred cells against the tumor. We will determine the role of host cells in tumor rejection using recipients lacking various lymphoid cell populations of mice deficient in various gene expression.
In AIM 3 we will investigate strategies for effective control of tumor growth. We will determine why the tumor grows after high tumor load and will test the hypothesis that the phenotype of the tumor is altered or that the CD8 cells become exhausted. We will determine what controls the growth in mice with low initial tumor load and will test the hypothesis that either CD4 or CD8 populations have a role in the control of the tumor cells.
