Heat Shock Protein-Peptide Interaction: Basis for a New Generation of Vaccines Against Cancers and Intracellular Infections

Abstract

The observations that inbred mice and rats can be immunized against their own tumors or against tumors of the same genetic background were convincingly made between 1943 and 1962 (Gross 1943; Foley 1953; Prehn and Main 1957; Klein et al. 1960; Old et al. 1962, for review, see Srivastava and Old 1988). They provided the underpinnings for the idea of immunogenicity of cancers and by deduction, of the existence of tumor-specific antigens. These studies showed that mice vaccinated with inactivated cancer cells are immune to subsequent challenges of live cancer cells. The phenomenon was shown to be individually tumor-specific, in that mice were resistant specifically to the tumors which were used to immunize them and not to other tumors (Basombrio 1970; Globerson and Feldman 1964), hence the name individually distinct tumor rejection antigens. The demonstration of immunogenicity of cancer cells led to a search for the cancer-derived molecules, which elicit resistance to tumor challenges. The general structure of these experiments was to fractionate cancer-derived proteins and test them individually for their ability to immunize mice against the cancers from which the fractions were prepared (see Srivastava and Old 1988; Old 1981, and Boon 1992 for other approaches to identification of tumor-specific antigens). The proteins of 96kDa, 90kDa and 70kDa size identified by the method (Table 1; Srivastava and Das 1984; Srivastava et al. 1986; Ullrich et al. 1986; Udono and Srivastava 1993) turned out to be related to a class of proteins known as heat shock proteins (hsps) or stress-induced proteins (see Lindquist and Craig 1988). Similar to the immunogenicity of intact tumor cells, it turned out that hsps gp96, hsp90 and hsp70 isolated from tumors were able to immunize and elicit protective immunity specifically against the tumors from which the hsps were isolated. Hsps isolated from normal tissues were found to be unable to elicit immunitv to any cancers tested.