Tumors and the immune system are engaged in a dynamical interplay, the outcome of which affects the survival of the host. Tumors have developed several different strategies to avoid elimination by the immune system. In many different tumor systems, it has been shown that there is a T cell dysfunction in tumor bearing hosts; however, the molecular basis for this dysfunction has not been established. It has also been clearly established in studies from our laboratory and several others that a T cell can interact with sub-optimal ligands, resulting in a variety of different outcomes, including anergy. The biochemical basis for this partial T cell activation has not been fully ascertained; however, there is a correlation with an altered TCRzeta phosphorylation pattern and lack of ZAP70 activation. Intriguingly, there is some biochemical data showing that a similar process may be occurring in tumor bearing hosts; however, a direct causal relationship has not been established. In these studies, we propose to ascertain definitively if there antigen specific T cell dysfunction in tumor bearing mice and explore the mechanisms involved. In the first aim, we propose to develop a TCR transgenic mouse system, utilizing the C18 T cell, which is specific for the methylcholanthrene induced CMS5 tumor. The antigenic epitope recognized by C18 has been identified to be a mutated ERK (136-144) bound to a H-2K/d molecule. We will also characterize how the T cells recognize the ERK(136-144) epitope and identify altered peptide ligands of it. In the second aim, we propose to investigate the role of T cell help in the generation of an anti-tumor response, utilizing a recently identified CMS- 5 specific class II epitope. In the third aim, we will develop a panel of unique antibodies specific for each phosphorylation events of TCRzeta during normal T cell activation. Once established, we will then compare and contrast these events with those occurring during partial T cell activation, with the goal being to establish the relationship between TCRzeta phosphorylation and T cell dysfunction. In the fourth aim, we will utilize the C18 TCR transgenic system and directly test the hypothesis that there is an antigen specific T cell dysfunction in tumor bearing mice. If a defect is found, we will then characterize the molecular basis of it, including the status of TCRzeta phosphorylation. Overall these studies will develop and utilize a unique tumor specific T cell system, which will provide us the opportunity to evaluate critically the existence and basis for T cell dysfunction in tumor bearing hosts.
| Matsui, Ken; O'Mara, Leigh A; Allen, Paul M (2003) Successful elimination of large established tumors and avoidance of antigen-loss variants by aggressive adoptive T cell immunotherapy. Int Immunol 15:797-805 |
| Krug, Anne; Uppaluri, Ravindra; Facchetti, Fabio et al. (2002) IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation. J Immunol 169:6079-83 |
| Dunn, Gavin P; Bruce, Allen T; Ikeda, Hiroaki et al. (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991-8 |
| Ikeda, Hiroaki; Old, Lloyd J; Schreiber, Robert D (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95-109 |
| Hanson, H L; Donermeyer, D L; Ikeda, H et al. (2000) Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13:265-76 |
