Cancer Immunology, Inflammation and Tolerance Program
Assistant Professor, Medicine
Assistant Professor, Graduate Studies
Assistant Professor, Biochemistry and Molecular Biology , Augusta University
Georgia Cancer Center
1410 Laney Walker Blvd., CN-4158A
The overall goal of our research is to understand how the innate immune system regulates adaptive immune responses to self-antigens, commensals, pathogens and harmless food antigens, and how these can be harnessed to treat immune-mediated inflammatory diseases, and in the development of vaccines to augment immune responses against tumors and mucosal pathogens.
Innate control of intestinal inflammation and inflammation-associated colon cancer. In the intestine, the immune system launches robust immunity against invading pathogens while maintaining a state of tolerance to commensal flora and ingested food antigens. However, the molecular mechanisms underlying this phenomenon remain poorly understood. Loss of immune tolerance to commensal flora results in chronic intestinal inflammation leading to inflammatory bowel disease (IBD) and IBD-associated colon carcinogenesis. Intestinal antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages (Mϕs) play a pivotal role in suppressing inflammation and in mediating immune tolerance to commensal flora. Despite their importance, significant gaps in our knowledge exist as to how intestinal APCs drive regulatory responses to contain inflammation and restore gut homeostasis. We are currently investigating the signaling networks and transcription factors that are critical for imparting a regulatory versus inflammatory phenotype on intestinal APCs. In addition, we are studying the molecular mechanisms by which innate immune cells regulate immune tolerance to orally fed antigens.
Dendritic cell control of chronic inflammation and autoimmunity. Dendritic cells (DCs) play a key role in both initiating immunity (immunogenic DCs) and regulating immune responses (regulatory DCs). Multiple subsets of DCs exist in both lymphoid and non-lymphoid tissues. Breakdown in the regulatory potential of DCs results in uncontrolled chronic inflammation, leading to autoimmunity. Despite their importance, significant gaps in our knowledge exist as to how DCs drive regulatory responses to contain or resolve chronic inflammation. In this context, our recent findings show that the canonical Wnt signaling pathway in APCs plays a critical role in controlling inflammatory responses and restoring immune homeostasis. We are currently investigating the downstream effector mechanisms by which the canonical Wnt pathway in lymphoid and myeloid DC subsets act to create tolerance and suppress inflammation and prevent autoimmunity.
Modulation of systemic immune responses by gut microbiota. Emerging data suggest that immune cells are critical in shaping the microbial composition in the gut3, 4. Accumulating evidences also suggest that gut microbiota can regulate not only the local intestinal immune system but also can have a profound influence on systemic immune responses5. Additionally, altered commensal microflora is inextricably linked to loss of immune tolerance to self-antigens, chronic systemic inflammation and autoimmunity3, 4, 6. Antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages (Mϕs) play a pivotal role in mediating immune tolerance, resolving inflammation and restoring homeostasis7, 8. How instructive signals from commensal microflora shape innate and adaptive immune responses at systemic sites are totally unknown. In this context, we are currently investigating mechanism by which APCs regulate commensal homeostasis and its influence on systemic immune responses.
Tumor microenvironment and immune suppression. Tumors actively suppress host immune responses. This represents a fundamental barrier to cancer immunotherapy as tumors expressing self-antigens actively suppress host immune responses. Accumulating evidence suggests that antigen presenting cells (APCs) such as dendritic cells (DCs) in the tumors and tumor draining lymph nodes (TDLNs) play a pivotal role in mediating immune suppression. However, the molecular mechanisms underlying this phenomenon remain poorly understood. The tumor microenvironment (TME) contains high levels of the Wnt family ligands, and aberrant Wnt-signaling occurs in many tumors. While most studies have been directed towards how the Wnt signaling cascade regulates cancer development, progression and metastasis, its effect on host anti-tumor immunity and tumor-induced immune tolerance remain unknown. In related work, we showed that Wnt-mediated activation of β-catenin in DCs induces retinoic acid production and suppresses immune responses against tumor-associated antigens (TAAs). We are currently investigating the downstream effector mechanisms by which the canonical Wnt and RA-RXR pathways in APCs suppress host immune responses against tumors. The information gained from these studies will provide fundamental mechanistic foundation for the therapeutic manipulation of the RA-RXRα and β‑catenin/TCF pathway specifically targeting DCs to enhance immune responses against tumors.
Innate control of adaptive immune responses to pathogens. Early innate immune responses to infectious agents largely determine the outcome of the infection and survival of the host. The innate immune system relies on a diverse array of receptors such as TLRs, C-type lectin receptor (CLRs), RIG-I like receptors (RLRs), and Nod-like receptors (NLRs) that can recognize a wide range of microbial structures and activate innate immune responses in a variety of cells, including DCs. Furthermore, there are several examples of how pathogens have evolved to modulate DCs to induce Tregs as an immune evasion strategy while preventing host immunopathology. The major goals are to understand how the Wnt pathway in APCs shapes innate and adaptive immune responses against mucosal pathogens such as influenza virus, Salmonella, and Candida albicans. These studies will help in the generation of better vaccine strategies to enhance immunity against pathogens.
Manicassamy S, Ravindran R, Deng J, Oluoch H, Denning TL, Kasturi SP, Rosenthal KM, Evavold BD, Pulendran B. (2009) Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med.15(4):401-9.
Manicassamy S, Pulendran B. (2009) Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages. Semin Immunol. 21(1):22-7.
Manicassamy S, Pulendran B. (2009) Modulation of adaptive immunity with Toll-like receptors.Semin Immunol. 21(4):185-93.
Manicassamy S, Reizis B, Ravindran R, Salazar-Gonzalez RM, Wang Y, Pulendran B. (2010) β-Catenin activation in dendritic cells is a molecular switch for immunity versus tolerance in the intestine. Science. 329(5993):849-53.
Pulendran B, Tang H, Manicassamy S. (2010) Programming dendritic cells to induce Th2 and tolerogenic responses.Nature Immunology.11(8):647-55.
Manicassamy S, Pulendran B. (2011) Dendritic cell control of tolerogenic responses. Immunol Rev. 241(1):206-27.
Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. (2014) TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. Journal of Immunology.193(8):4203-13.
Hong Y, Manoharan I, Suryawanshi A, Majumdar T, Angus-Hill ML, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. (2015) β-catenin promotes T regulatory cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Research. 75(4):656-65.
Suryawanshi A*, Manoharan I*, Hong Y, Swafford D, Majumdar T, Taketo MM, Manicassamy B, Pandelakis KA, Thangaraju M, Sun Z, Mellor AL, Munn DH and Manicassamy S (2015). Canonical Wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. Journal of Immunology, 194 (7).
Hong Y*, Manoharan I*, Suryawanshi A, Majumdar T, Angus-Hill ML, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. (2015). β-catenin promotes T regulatory cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Research 75(4):656-65. (* co-first authors).
Hong Y*, Manoharan I*, Suryawanshi A , Swafford D, Ahmad S, Chinnadurai R, , Manicassamy B, He Y, Mellor AL, , Sun Z, Munn DH, Thangaraju M, Manicassamy S. Deletion of LRP5 and LRP6 in dendritic cells enhances anti-tumor immunity. OncoImmunology (Accepted) (* co-first authors).
Suryawanshi A and Manicassamy S (2015). Tumors induce immune tolerance through activation of β-catenin/TCF4 signaling in dendritic cells – A Novel Therapeutic Target for Cancer Immunotherapy. Oncoimmunology.
Manoharan I, Hong Y, Suryawanshi A, Manicassamy B, Thangaraju M, Manicassamy S. (2016). PPARα signaling in innate immune cells is critical for regulating commensal homeostasis and intestinal inflammation. Journal of Immunology 195(11):4739-49.