In Situ Signals from Tumor-Infiltrating Monocyte-Derived Dendritic Cells are Required to Elicit T Cell Cytotoxicity

​

Yaron Carmi, Gray Faculty of Medical and Health Sciences

​

The signals by which dendritic cells (DC) promote activation of cytotoxic T cells have been the focus of immunology research for over half a century. Yet, attempts to employ our current understanding of DC-T cell interactions to treat established tumors have achieved only limited success in clinical trials. Hence, we performed an in-depth analysis of the transcriptomic and functional changes that CD8+ T cells undergo following interactions with DC subsets in the lymphoid organs and tumor bed. As a result, we generated a detailed description of their trajectory from naïve to fully cytotoxic effector cells. We found that antigen presentation to CD8+ T cells is predominantly mediated in lymphoid organs by classical DC, but it is not sufficient to elicit cytotoxicity. Instead, antigen-experienced CD8+ T cells must receive additional inflammatory signals, predominantly through TNF, at tumor sites from infiltrating myeloid DC. Synchronization of these two activation modules is requisite for eliciting T cell cytotoxicity. While vaccinations with DC activated and pulsed with tumor-antigens do induce tumor-reactive CD8+ T cells in lymphoid organs, these DC rapidly lose their expression of TNF upon infiltration into the tumor bed, resulting in limited T cell cytotoxicity.
   Beyond identifying the molecular axis, this work proposes a novel immunological concept of activation, where sequential signals provided in a time-dependent manner to T cells by different DC at different anatomical sites govern T cell cytotoxicity. Finally, these findings open a new therapeutic framework to increase the potency of cancer DC vaccines.