Regulation of DC Activity by Memory and Effector CD8+ T Cells

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In the previous (first) period of funding of this project we demonstrated that memory and effector CD8+ T cells exert reciprocal, DC-killing (“suppressive”) versus DC-activating (“helper”) activities and differentially affect the immunologic and anti-tumor activity of cancer vaccines. Our data demonstrate that effector CD8+ T cells kill antigen (Ag)-bearing DCs in a perforin (Pfn)- and Granzyme B (GrB)-dependent mechanism. In contrast, memory CD8+ T cells play a “helper” role, inducing the DC expression of the serpin PI9 (CAP3/B9/SPI6), an endogenous GrB inhibitor, and protecting DCs from cytotoxic T cell (CTL)-mediated killing. They also induce type-1 polarization of DCs, manifested by their enhanced production of IL-12p70, enhanced ability to support Th1- and CTL responses and to mediate antitumor effects. Moreover, we have demonstrated that the nominally “suppressive” effector CTLs can be converted to “helper cells” following pharmacologic blockade of their cytolytic machinery, or following their TCR-independent activation with IFNα plus IL-18. Based on these data, we hypothesize that the elimination of tumor-associated antigen (TAA)-harboring DCs by the TAA-specific CTLs is a significant factor limiting the prolonged effectiveness of therapeutic cancer vaccines. Furthermore, we hypothesize that the ability of memory CD8+ T cells to activate DCs and protect them from the effector cell-induced apoptosis can be utilized to increase the continued effectiveness of vaccination. In the next period of funding, we propose to test the above hypotheses and to develop means to counteract the suppressive impact of pre-existing tumor-specific CD8+ T cells and to utilize their “helper” potential in the following Specific Aims: 1. Identify the molecular mechanisms of DC-killing and DC protection/polarization by human CD8+ effector (Teff) versus memory (Tmem) cells, as potential targets of immunointervention. 2. Validate the key mechanisms of DC modulation by mouse CD8+ Teff and Tmem cells in vitro. Success of tehse studies will allow us to optimally design prospective in vivo mouse studies testing the relative contribution of the individual regulatory mechanisms to the Teff -and Tmem-mediated immune regulation in vivo and to develop strategies to counteract the CTL-mediated DC killing elimination and to utilize the CD8+ T cell-dependent help in mouse models of therapeutic cancer vaccination. The positive outcome of this project and it follow-up studies, will help us to understand basic principles of immune memory and regulatory functions of Teff and Tmem cells, and will allow us to develop new off-the-shelf therapeutic cancer vaccines and combined cancer therapies utilizing the principles of protection and polarization of endogenous DCs of cancer patients, in order to achieve continued immunologic and therapeutic effects of vaccination against established cancer.