The major goal of this Program Project is to define the molecular basis of four processes used by tumors to escape detection and destruction in immunocompetent hosts. To achieve this goal we have proposed an integrated and coordinated research program that consists of three projects and three cores. Recent work from the laboratory of Robert Schreiber has shown that recognition of tumors by the immune system often is dependent on a change induced in the tumor cell itself through the action of IFNgamma. Tumors which become (or are made) INFgamma insensitive through genetic or acquired mechanisms remain invisible to the immune system and thereby acquire the capacity to grow progressively in naive or immune hosts. Project 1 thus seeks to define the role of IFNgamma in promoting tumor immunogenicity and to elucidate the genetic and adaptive mechanisms used by tumors to circumvent this process. Recent work from the laboratory of Andry Shaw has identified a novel T cell surface protein known as CD2AP that interacts with the T cell accessory molecule CD2 and facilitates CD2 clustering and concentration during T cell activation. Project 2 thus seeks to determine the mechanism underlying CD2AP function, analyze the function of CD2 clustering in T cell activation and then determine the requirement for CD2 in promoting tumor immunity. Recent work in the laboratory of Paul Allen has shown that T cell receptor stimulation by peptide-MHC complexes can induce a continuum of responses that range from full T cell activation to T cell paralysis. Partial T cell activation may explain some aspects of T cell dysfunction observed in other tumor model systems. Project 3 thus will seek to develop a model system to unequivocally established whether tumor bearing mice develop antigen specific T cell dysfunction and then relate the molecular basis of this process to partial T cell activation. Together this work will provide new insights into host-tumor relationships that would help in developing new strategies for the treatment of cancer.
| 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 |
