One of the most critical questions in cancer immunology is why the immune system fails to eliminate tumors that arise de novo. Concentrating on the T cell-mediated immune response, we sought to determine whether this was due to an absence of CTL precursors capable of recognizing tumor-specific neoantigens or rather, a failure of the helper arm to produce the lymphokines that act as critical second signals for CTL activation. We devised a novel strategy to answer this question that involved engineering tumor cells by gene transfection to produce helper lymphokines known to be important for CTL priming. The critical feature of this approach is that the helper lymphokine is produced only where the antigens are. We reasoned that these engineered tumors might effectively prime """"""""latent"""""""" tumor specific CTL by bypassing a defective T helper arm. Indeed, we found that animals injected with poorly immunogenic tumors engineered to secrete IL-2, IL-4 or GMGSF developed systemic immunity against challenge with the parental tumor. The broad objective of this proposal is to dissect the antitumor immune response generated by immunization with lymphokine gene-transfected tumors at the cellular and molecular level. In particular, the following aims will be pursued: 1) To characterize the mechanisms by which tumor antigen-specific CTL are primed. We propose a set of experiments to determine the role of each of the infiltrating cells in the priming of CTL in vivo and to distinguish whether MHC class I-restricted tumor antigens are presented by the engineered tumor itself or by bone marrow-derived antigen-presenting cells 2) We plan to use T cell receptor transgenic mice expressing identifiable T cell receptors reactive with tumor-specific helper antigens presented on MHC class II molecules to determine why the helper arm of the immune system apparently fails to function in the antitumor response 3) We plan to further explore the immune response to tumors that have turned off their MHC class I antigens 4) We plan to use tumor-specific CTL to identify tumor specific peptide-epitopes which will ultimately be purified and sequenced.
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