Cancer Immunology, Inflammation & Tolerance
Andrew Mellor, MA, PhD
Co-Leader, Cancer Immunology, Inflammation and Tolerance Program
1120 15th Street, CN 4151
Research in the Mellor Laboratory focuses on chronic inflammatory diseases. Local inflammation caused by tumor growth blocks immune responses capable of destroying malignant cells. The reverse process takes place during development of autoimmune diseases when natural tolerance of healthy tissues breaks down allowing immune cells to destroy tissues. We use a broad range of techniques to study inflammatory and immunologic processes that contribute to disease progression in mouse models of cancer and autoimmune diseases. In addition we have long term interests in studying chronic infections, which as in cancer arise when host immunity is curtailed, allowing infectious pathogens to persist and cause chronic disease.
The role of DNA in metabolic control of immunity and autoimmunity:
DNA is widely recognized as a potent immune stimulant because DNA sensors trigger pro-inflammatory cytokine release when DNA is sensed. DNA sensing is a key factor in host defense to pathogens, providing an early warning of infection. In 2011 we discovered that cargo DNA from DNA nanoparticles (DNPs) was sensed to inhibit immunity and alleviate autoimmune disease syndromes in mice. Specialized innate immune cells sensed DNP cargo DNA via cytosolic DNA sensors that activate the adaptor STING (Stimulator of Interferon Genes) to induce interferon (IFN) and expression of indoleamine 2,3 dioxygenase (IDO), a potent natural immune suppressant. Moreover, DNA from dying cells is also sensed to activate the STING/IFN pathway and induce potent tolerogenic responses mediated by IDO. These findings suggest that dying cells release DNA that is sensed to prevent autoimmunity.
The role of DNA from dying tumor cells in the tumor microenvironment (TME):
Based on novel findings described above, we initiated a new project to test if DNA from dying tumor cells is sensed to facilitate tumor growth by inducing IDO in the TME. Abnormally elevated IDO activity is common in TMEs of mice and cancer patients, consistent with the emerging paradigm that IDO is a ‘checkpoint’ that impedes natural and vaccine induced anti-tumor immunity. In ongoing studies we are studying requirements to induce IDO in the TME using mouse models of tumor growth. Goals are to elucidate the critical pathways in innate immune cells associated with tumors that drive immune regulation to facilitate tumor formation. These studies have potential to reveal novel targets for early interventions designed to impede tumor progression prior to overt tumor formation.
Metabolic control of inflammatory responses in the colon following radiation exposure:
In collaboration with Dr. Khleif and other Georgia Cancer Center faculty we developed a large NIH program grant application to identify novel diagnostic biomarkers of radiation exposure and to evaluate novel medical countermeasure drugs to alleviate tissue damage caused by radiation exposure and promote survival. We found that lethal radiation exposure stimulated highly localized IDO activity in the gastro-intestinal (GI) tract of mice and that mice lacking IDO genes were more susceptible to the harmful effects of radiation exposure. These novel findings suggest that metabolic regulation of inflammatory responses to radiation is a critical factor in alleviating tissue pathology and promoting survival. This project has the potential to identify novel ways to alleviate harmful side effects of radiotherapy to treat cancer, to elucidate fundamental mechanisms driving cancer formation in the GI-tract, and to evaluate novel checkpoint blockade reagents (including IDO inhibitors) as potential medical countermeasure drugs to alleviate harmful effects arising from radiation exposure.
Chronic retroviral infections and leukemogenesis:
Many retroviruses such as Human Immunodeficiency Virus-1 (HIV1, the virus that causes AIDS) have evolved to persist in immunocompetent hosts. It is not clear how retroviruses suppress host immunity to persist though abnormally high IDO activity is a common factor in chronic HIV-1 infection in humans and murine leukemia virus (MuLV) infection in mice, which replicates some aspects of HIV-1 infections, including progressive immune deficiency and increased risk of cancer. In ongoing studies we found that MuLV infection induces IDO activity in a specialized subset of antigen presenting cells (APCs) in mouse spleen, which expand in number as disease progresses. Goals are to elucidate the underlying processes that allow MuLV to persist and evade host immunity in mice, and identify novel targets for intervention that enhance anti-viral immunity and reduce the risk of virus induced carcinogenesis.
Johnson BA, Kahler DJ, Baban B, Chandler PR, Kang, B, Shimoda M, Koni PA, Pihkala J, Busslinger M, Vilagos B, Munn DH, Mellor AL. (2010) B-lymphoid cells with attributes of dendritic cells regulate T cells via IDO. Proc Natl Acad Sci USA. 107:10644-8.
Sharma MD, Hou D-Y, Baban B, Koni PA, He Y, Blazar BR, Mellor AL, Munn DH. (2010) Reprogrammed Foxp3+ Tregs provide essential help to support cross-presentation and CD8+ T cell priming in naive mice. Immunity. 33:942-54.
Ravishankar B, Liu H, Schinde R, Chandler PR, Baban B, Tanaka M, Munn DH, Mellor AL, Karlsson MC, McGaha TL. (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3 dioxygenase. Proc Natl Acad Sci USA. 109:3909-14.
Huang L, Lemos, H, Li L, Li M, Chandler PR, Baban B, McGaha TL, Ravishankar B, Lee J, Munn DH, Mellor AL. (2012) Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. J Immunol. 188:4913-20.
Munn DH, Mellor AL. (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34:137-43.
Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, Shi H, Munn DH. (2013) An inherently bi-functional subset of Foxp3+ Treg/T-helper cells is controlled by the transcription factor Eos. Immunity. 38:998-1012.
1Huang L, 1Li L, Klonowski KD, Tompkins SM, Tripp RA, Mellor AL. (2013) Induction and role of indoleamine 2,3 dioxygenase in mouse models of influenza A virus infection. PLoS One. 8:e66546. ( Co-first authors)
1Huang L, 1Li L, Lemos H, Chandler PR, Pacholczyk G, Baban B, Barber GN, Hayakawa Y, McGaha TL, Ravishankar B, Munn DH, Mellor AL. (2013) Cutting Edge: DNA Sensing via the STING Adaptor in Myeloid Dendritic Cells Induces Potent Tolerogenic Responses. J Immunol. 191:3509-13. ( Co-first authors)
Ravishankar B, Shinde R, Liu H, Chaudhary K, Bradley J, Lemos HP, Chandler PR, Tanak M, Munn DH, Mellor AL, McGaha TL. (2014) Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci USA. 111:4215-20.
Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH, Mellor AL. (2014) Activation of the Stimulator of Interferon Genes (STING) adaptor attenuates experimental autoimmune encephalitis. J Immunol. 192:5571-8.
Hong Y, Manoharan I, Suryawanshi A, Majumdar T, Angus-Hill A, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. (2015) β-catenin induces vitamin A metabolism in dendritic cells to promote T regulatory responses to tumors. Cancer Research. In Press.
Lemos H, Huang, L, McGaha TL, Mellor AL. (2015) STING, nanoparticles, autoimmune disease and cancer; a novel paradigm for immunotherapy? Expert Rev Clin Immunol. 11:155-65.