Much of current Cancer Immunology is concerned with the identification of tumor antigens and with vaccine strategies to elicit responses to those antigens. We focus here, however, on how tumor cells are killed and why immune responses often fail. Adoptively transferred in vitro generated Tc1 or Td2 CDS effectors from tumor specific T cell receptor transgenic mice can eliminate established tumors in several tumor models. These same cells kill tumor targets in vitro by perforin mediated cytolysis yet effectors generated from perforin deficient mice are as effective as effectors from wildtype mice upon adoptive transfer. It is thus unclear what mechanisms are involved in the control tumor growth by the adoptively transferred CDS effectors in either the initial tumor reduction or in the subsequent prevention of re-growth, This will investigated in AIM 1. Adoptive transfer of large numbers of naive tumor specific CDS transgenic T cells fail to control the growth of established tumors in the same model. We have shown that these naive cells proliferate in response to the tumor antigen in vivo but fail to limit tumor growth. The basis for the difference in the efficacy between in vitro and in vivo stimulated cells will be investigated in AIM 2. Our tumor model is the ova expressing EG7 and the CDS T cells we use come from the ova specific TcR transgenic OT-1 mice.
In AIM 1. we will determine how CDS T cells control tumor growth in the adoptive transfer model. We will determine the CDS effector dependent killing mechanisms in both the initial tumor reduction (phase 1). A knowledge of what actually reduces tumor growth is essential in designing appropriate therapeutic procedures.
In AIM 2. we will determine why the response of host cells is much less able to control tumor growth compared with adoptive transfer of in vitro generated effectors. The implications for therapy are quite different according to which possibility is correct. An understanding of the precise mechanisms involved the control of tumor growth, and of why the unaided immune response is ineffective will further the design of effective anti-tumor therapy.
