Tumors are potentially immunogenic. However, they fail to spontaneously induce immune responses capable of^ rejecting tumors. A major reason for this is that the tumor microenvironment lacks adequate innate immune activation required to initiate strong adaptive antitumor immunity. Plasmacytoid dendritic cells (pDCs) are highly specialized in that they sense microbial nucleic acids via intracellular Toll-like receptors. During viral infection, pDCs accumulate in infected tissues and are activated by viral nucleic acids to produce large amounts of type I interferons (IFNs) and generate protective immunity against the virus by activating myeloid dendritic cells, T cells, and natural killer cells. Tumors also contain pDCs but do not provide molecular signals to activate pDCs, although tumors contain self-DNA released in the extracellular environment at high concentrations as a result of increaised turnover of tumor cells. pDCs, though activated by viral nucleic acids, clearly are normally not able to sense tumor-derived DNA and are thus unable to initiate strong innate immune responses. We recently found that pDCs can, in fact, sense and respond to self-DNA when combined with an endogenous peptide called LL37. LL37 can bind to self-DNA 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/self-DNA can interact with Toll like receptor 9 to trigger robust type I IFN production similariy to viral DNA. Because tumors release large amounts of self-DNA and contain pDCs but do not express LL37, our hypothesis for the proposed study described herein is that exogenous LL37 can be used to target tumor-derived self-DNA and convert it into a 'danger signal" that triggers pDC activation and type I IFN production at the tumor site in patients with melanoma. This then induces T-cell-mediated immunity against melanoma by using the same mechanism by which anti-viral-immune responses are induced. Therefore, we will pursue the followinig:
Specific Aim 1 : Determine the mechanism of anti-tumor immune responses induced by intratumoral LL37 injection in mouse tumor models;
Specific Aim 2 : Evaluate anti-tumor immune responses and clinical efficacy of intratumoral LL37 injection in patients with melanoma;
Specific Aim 3 : Improve anti-tumor immune responses and efficacy of intratumoral LL37 injection in mouse tumor models. These studies may lead to principles in cancer immunotherapy that may be vyidely applicable to other cancers.
Development and implementation of novel immunotherapeutic approaches to elicit potent anti-tumor immune responses to treat patients with melanoma is a key objective of this project. We will activate pDC in the melanoma microenvironment by administering LL37-derived peptides in order to generate a local and systemic antitumor immune response. This project combines basic and clinical research to use pDC activation at the tumor site as a novel immune strategy to enhance anti-melanoma immune responses.
|Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing et al. (2015) Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Clin Cancer Res 21:611-21|
|Fang, Shenying; Wang, Yuling; Chun, Yun Shin et al. (2015) The relationship between blood IL-12p40 level and melanoma progression. Int J Cancer 136:1874-80|
|Siroy, Alan E; Boland, Genevieve M; Milton, Denái R et al. (2015) Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol 135:508-15|
|Chattopadhyay, Chandrani; Grimm, Elizabeth A; Woodman, Scott E (2014) Simultaneous inhibition of the HGF/MET and Erk1/2 pathways affect uveal melanoma cell growth and migration. PLoS One 9:e83957|
|Sim, Geok Choo; Chacon, Jessica; Haymaker, Cara et al. (2014) Tumor-infiltrating lymphocyte therapy for melanoma: rationale and issues for further clinical development. BioDrugs 28:421-37|
|Rees, Elliott; Walters, James T R; Georgieva, Lyudmila et al. (2014) Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry 204:108-14|
|Lopez-Rivera, Esther; Jayaraman, Padmini; Parikh, Falguni et al. (2014) Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. Cancer Res 74:1067-78|
|Boraska, V; Franklin, C S; Floyd, J A B et al. (2014) A genome-wide association study of anorexia nervosa. Mol Psychiatry 19:1085-94|
|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|
|Wang, Yun; Hu, Shougang; Gabisi Jr, Abdul M et al. (2014) Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma. ChemMedChem 9:792-7|
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