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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Texas MD Anderson Cancer Center
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Huang, L; Wang, Z; Liu, C et al. (2017) CpG-based immunotherapy impairs antitumor activity of BRAF inhibitors in a B-cell-dependent manner. Oncogene 36:4081-4086
Peng, Weiyi; Chen, Jie Qing; Liu, Chengwen et al. (2016) Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16
Meller, Stephan; Di Domizio, Jeremy; Voo, Kui S et al. (2015) T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol 16:970-9
Singh, Manisha; Overwijk, Willem W (2015) Intratumoral immunotherapy for melanoma. Cancer Immunol Immunother 64:911-21
Lande, Roberto; Chamilos, Georgios; Ganguly, Dipyaman et al. (2015) Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self-DNA. Eur J Immunol 45:203-13
Singh, Manisha; Khong, Hiep; Dai, Zhimin et al. (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722-31
Hailemichael, Yared; Overwijk, Willem W (2013) Peptide-based anticancer vaccines: The making and unmaking of a T-cell graveyard. Oncoimmunology 2:e24743
Radvanyi, Laszlo; Pilon-Thomas, Shari; Peng, Weiyi et al. (2013) Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer--letter. Clin Cancer Res 19:5541
Hailemichael, Yared; Dai, Zhimin; Jaffarzad, Nina et al. (2013) Persistent antigen at vaccination sites induces tumor-specific CD8? T cell sequestration, dysfunction and deletion. Nat Med 19:465-72
Yang, Yan; Liu, Chengwen; Peng, Weiyi et al. (2012) Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood 120:4533-43

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