Although cancer vaccines offer significant promise, clinical effectiveness has yet to be realized. Effective vaccines may require inclusion of basic elements of the immune response which allow successful elimination of pathogens. It is now clear that strong adaptive immune responses are preceded by a potent innate immune response, triggered by pathogen-associated molecular patterns (PAMPs) that are recognized by immune cells expressing Toll-like receptors (TLRs). In the absence of TLR signaling, release of inflammatory cytokines by innate immune cells is sub-optimal. Tumor cells typically do not trigger TLR signaling and this contributes to the lack of effective antigen-specific immunity in solid tumors. Harnessing and adapting the mechanisms used by pathogens to induce effective immunity represents a very promising approach to improving antigen-specific antitumor immune responses. The plasmacytoid dendritic cell, the primary producer of type I interferons in the body, is a central mediator of anti-viral innate immunity and coordinates immune cell interactions which lead to a potent adaptive T-cell response. This innate immune response is important not only to trigger strong T-cell priming, but also to induce inflammation at the target site which leads to enhanced T-cell migration and effector function. In our murine models, we have found that plasmacytoid dendritic (pDC) cells can lead to enhanced antigen-specific immune responses, partially through synergy with myeloid dendritic cells (mDC). In addition, we and others have found that pDC can be activated directly in vivo through specific TLR ligands. In this proposal, we will test these concepts in melanoma patients and will utilize a vaccine in combination with a TLR agonist capable of activating both pDC and mDC in order to model the synergy observed in our murine system. We will measure T-cell priming in patients immunized in the presence or absence of TLR activation. Subsequent to T-cell priming, we will administer a TLR agonist at the tumor site in order to induce inflammation. We will test the ability of this intervention to activate pDC and mDC at the tumor site and enhance T-cell migration into the tumor and Tcell effector function. Specifically, we will: 1) Evaluate T-cell priming following immunization in the presence or absence of TLR activation at the vaccine site, 2) Analyze the tumor microenvironment following TLR administration at the tumor site, and 3) Correlate clinical response with T-cell priming and the activation state of immune cells within the tumor microenvironment. By applying principles learned from our basic understanding of immune reactions facilitated by TLR signaling during successfully controlled viral infections, our goal is to develop improved antitumor responses. In addition, these studies may lead to strategies which may be generalized towards improving cancer vaccines against other common cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
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

Showing the most recent 10 out of 23 publications