Sultan, Hussein Mohammed Hussein; Department of Biochemistry and Molecular Biology / Cancer Center (2017)
      Cytotoxic T lymphocytes (CTLs) are the most effective components of the immune system capable of destroying tumor cells. The identification of CTL tumor epitopes has led to numerous clinical studies in the form of therapeutic vaccines, but the overall immune responses and the antitumor effects of these vaccines have been suboptimal. Previously, The Celis laboratory reported that vaccines prepared with palmitoylated peptides mixed with poly-IC (BiVax) generate strong CTL responses. Poly-IC, a synthetic double stranded RNA, activates both toll like receptor 3 (TLR3) and cytoplasmic melanoma differentiation associated protein 5 (MDA5). Although TLR3 was essential for the priming phase, poly-IC mediated MDA5 activation was critical for the subsequent expansion of the primed T cells upon antigen reencounter (boosting). However, the role of different antigen presenting cells, MDA5 activation and the requirement of type I interferon (IFN-I) and other T cell stimulatory cytokines remained unclear. Here, I describe how dendritic cells (DCs) are essential for palmitoylated peptide presentation and how MDA5 activation regulates the production of IFN-I, which enhances T cell responses indirectly through inducing IL15 and/or IL2 production. Furthermore, blocking IL2 or IL15 signaling inhibited T cell expansion resulting from BiVax immunization. The combination of BiVax with sustained IL2 signaling (provided by administration of IL2/IL2 antibody complexes (BiVax/IL2Cx) or pegylated IL2 generated large endogenous T cell responses that effectively control tumor growth. Furthermore, sustained IL2 signaling improved the inherent ability of antigen specific T cells to resist inhibitory PD-1 signaling. The antitumor effects of BiVax/IL2Cx were associated with severe autoimmune diabetes when using an antigen expressed by the tumor and the pancreas. These symptoms could be avoided while preserving outstanding antitumor responses by utilizing a tumor antigen that is not expressed in the pancreas. Collectively, my study provides a clear evidence that IFN-I and IL2 are important in mediating T cell expansion and enhancing the antitumor effects of peptide-based vaccines. First and foremost, most of the vaccine components have been used in the clinic, and applying this vaccination approach for cancer treatment can be attainable.