Cancer Immunology, Inflammation and Tolerance Program
Associate Professor, Medicine,
Associate Professor, Pathology
Associate Professor, Biochemistry and Molecular Biology
Associate Professor, Graduate Studies
Georgia Cancer Center
1410 Laney Walker Blvd.,CN 4154
Augusta, GA 30912
Email: pkoni@ augusta.edu
My laboratory does research on the immune system to discover how it normally maintains a balance between combating infectious disease and being tolerant of our own body as well as innocuous, environmental exposures. Sometimes, this balance is perturbed with an unfavorable outcome, such as in autoimmune disease, and sometimes these mechanisms are taken advantage of to allow tumor growth relatively unchecked. My goal is to develop new therapeutics that take advantage of the immune system, bypassing normal roadblocks that the immune system normally places on itself or that it is exposed to in tumors, in order to treat and eradicate cancer. At the same time, in collaboration with colleagues, my research aims to apply what we learn to do what could be said to be the converse, to eliminate aggression against our own body that is seen in autoimmune diseases.
My research aims to improve our understanding of the molecular mechanisms whereby the immune system is regulated and how this knowledge might be translated into new therapeutics for the treatment of cancer or autoimmunity. One project is concerned with antigen-presenting cells in the gut in maintaining tolerance to innocuous food allergens and how they are influenced in the gut by dietary fiber products both in health and in mouse models of inflammatory bowel disease. More specifically, we have generated conditional knockout mice of the short chain fatty acid transporter, SLC5A8; these mice are being studied in inflammatory diseases and tumor models both in the gastrointestinal system and at other sites where short chain fatty acids and their transport may play a significant role in normal physiology as well as cancer. Collaborations with close colleagues have also resulted in recent publications concerning immune tolerance mechanisms in the gut mediated via Wnt factors and beta-catenin signaling, among others, and are being further investigated.
A relatively new project that is being funded by pilot project funds is a translational research project that aims to render T cells resistant to multiple forms of cell surface receptor-mediated immunosuppression simultaneously. If testing using in vitro models supports proceeding, the next goal will be to apply our new technology in a mouse tumor model using tumor-reactive TCR transgenic CD8 T cells to test for increased tumor regression and cure. The goal is to make it possible for CAR-T, ADCR-T or any other form of adoptive T cell transfer to cause regression of even solid tumors. That is, this approach could conceivably be applied no matter the source of CD8 T cells (e.g., TCR transgenic, ADCR-T, CAR-T or even de novo tumor-derived CD8 T cells).
Manoharan I., Suryawanshi A., Swafford D., Hong Y., Ahmad S., Ramesh G., Manicassamy B., Koni P.A., Thangaraju M. and Manicassamy S. (2016). Homeostatic PPARα signaling limits inflammatory responses to commensal microbiota in the intestine. J. Immunol. 196: 4739-49 (2016).
Suryawanshi A., Manoharan I., Hong Y., Swafford D., Tanmay Majumdar T., Taketo M.M., Manicassamy B., Koni P.A., Thangaraju M., Sun Z., Mellor A.L., Munn D.H. and Manicassamy S. (2015). Canonical Wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation. J. Immunol. 194: 3295-304.
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 Res.15:656-65.
Geem D, Medina-Contreras O, McBride M, Newberry RD, Koni PA, Denning TL. (2014) Specific microbiota-induced intestinal Th17 differentiation requires MHC II but not GALT and mesenteric lymph nodes. J. Immunol.193:431-8.
Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, Wherry EJ, Koni PA, Bushman FD, Elson CO, Eberl G, Artis D,Sonnenberg GF. (2013) Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 498:113-7.
Koni PA, Bolduc A, Takezaki M, Ametani Y, Huang L, Lee JR, Nutt S, Kamanaka M, Flavell RA, Mellor AL, Tsubata T, Shimoda M. (2013) Constitutively CD40-activated B cells regulate CD8 T cell inflammatory response by IL-10 induction. J. Immunol.190:3189-96.
Sharma MD, Hou DY, Baban B, Koni PA, Chandler PR, Blazar BR, Mellor AL, Munn DH. (2010) Reprogrammed Foxp3+ regulatory T cells provide essential help to support cross-presentation and CD8+ T cell priming in naive mice. Immunity. 33:942-54.