Heat shock proteins (HSPs) and hyperthermia have proven to stimulate anti-tumor immunity. The current application will address the interaction HSPs and heat at the level of antigen presenting cells (APCs). Large HSPs, i.e., hsp110 and grp170, are molecular chaperones that are highly efficient in binding to large substrate proteins. In the previous funding period we demonstrated that clinically relevant tumor protein antigens (e.g., gp100, HER-2/neu, etc.) can be used to generate highly effective antigen-specific, anti-tumor immunity when they are complexed to these large HSPs by heat shock. The vaccine potency of other exogenously delivered HSP-antigen complexes has been attributed to the specific interaction between HSPs and receptors on APCs. Since ligands of scavenger receptors (SRs) like fucoidan block hsp110 binding to APCs and inhibit vaccine activity, we began to investigate the SR family of receptors. However, in our initial work we observed that the absence of scavenger receptors-A (SR-A) in a knock-out mouse model significantly enhanced (rather than diminished) hsp110 vaccine-generated immunity against tumors. This suggests that at least this HSP binding receptor (SR-A) is an inhibitory receptor that can interfere with the immunostimulatory activities of HSPs in vivo. Based on these findings, we hypothesize that selective scavenger receptor engagement may lead to highly distinct immunological consequences. In the physiological setting, these differing receptor-mediated outcomes (e.g., inhibitory or stimulating) may help to balance and generate appropriate responses of APCs. Molecular and immunological understanding of the precise outcomes of HSP- receptor interactions on APCs could provide new strategies for enhancing weak or defective immune responses against tumors. To test our hypothesis we propose the following specific aims: 1) To dissect immune regulatory roles of SR-A in hsp110-antigen chaperone complex induced antigen-specific immune responses. 2) To determine whether down-regulation of SR-A in antigen-presenting cells improves hsp110 chaperone complex generated anti-tumor immunity. 3) To identify the contributions of other hsp110-interacting scavenger receptors (SRs) to hsp110-mediated immune activation and (based on other new preliminary data) determine whether mild thermal stress can modulate the interaction between SRs and HSPs. Overall, these studies will identify the specific contributions of SRs to hsp110-antigen complex elicited antigen-specific anti-tumor immunity, which could provide novel approaches targeting immunosuppressive receptors to enhance hsp110 chaperone vaccine potency. They will also provide insight into the role of thermal stress in the modulation of this interaction. Knowledge of modulation of these SRs by mild thermal stress could be exploited therapeutically to improve HSP vaccine efficacy by hyperthermia for the treatment of cancer.
The project proposes to study the mechanisms that regulate a cancer vaccine that is based on a large heat shock protein called hsp110. The studies concentrate on a group of receptors for hsp110-tumor antigen complexes that are expressed on antigen presenting cells (APCs), the sentinel cells of the immune system. Some of these receptors stimulate an anti-tumor immune response while others can inhibit it. The project will examine the immune-regulatory activity of each of these receptors on APCs and how mild, fever range hyperthermia can modify these activities.
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