Tumors are potentially immunogenic;however, they fail to spontaneously induce an immune response capable of rejecting the tumor. A major reason is that the tumor microenvironment lacks adequate innate immune activation required to initiate strong adaptive anti-tumor immunity. Plasmacytoid dendritic cells (pDC) comprise a dendritic cell subset highly specialized in sensing microbial nucleic acids via intracellular Toll-like receptors. During viral infection, pDC accumulate in infected tissues and are activated by viral nucleic acids to produce large amounts of type I IFNs and generate protective immunity against the virus through activation of myeloid DCs, T cells, and NK cells. Tumors also contain pDCs, but do not provide the molecular signals to activate pDCs. Although tumors contain high concentrations of self-DMA released in the extracellular environment as a result of the increased turnover and tumor cell death, it is clear that pDCs, while activated by viral nucleic acids, are normally not able to sense tumor-derived DMA and are thereby unable to initiate a strong innate immune response. We recently found that pDC can, in fact, sense and respond to self-DMA when combined with an endogenous peptide called LL37. LL-37 can bind self-DMA fragments released by dying cells to form aggregates and condensed structures that are delivered to and retained within early endosomes of pDCs. In these intracellular compartments, LL37/DNA can interact with TLR9 to trigger robust type I IFN production similarly to viral DMA. Because tumors release large amounts of self-DMA and contain pDCs but do not express LL37, our hypothesis is that exogenous LL37 can be used to target tumor-derived self-DMA and convert it into a """"""""danger signal"""""""" that triggers pDC activation and type I IFN production at the tumor site. This will then induce T-cell mediated immunity against the tumor by the same mechanism by which anti-viral immune responses are induced.
Specific Aim 1 will determine whether LL37 can convert self-DMA released by dying tumor cells from being immunologically inert into a trigger of pDC activation to produce type I IFNs.
Specific Aim 2 will evaluate whether LL37 mixed with dying tumor cells ex-vivo and injected in-vivo as a vaccine can induce effective T cell-mediated anti-tumor immunity.
Specific Aim 3 will assess whether dying tumor cells releasing self-DMA can be targeted by intratumoral injection or systemic administration of LL37 to induce innate immune activation at the tumor site leading to effective anti-tumor immunity. These studies may lead to the design of future clinical trials utilizing LL37 in cancer patients with diffusely metastatic disease.
Showing the most recent 10 out of 23 publications
