Giorgio Trinchieri, M.D.
NIH Distinguished Investigator
Cancer and Inflammation Program
Building 37, Room 4146A
Bethesda, MD 20892
Role of Inflammation, Innate Resistance, and Immunity in Carcinogenesis, Cancer Progression, and Prevention or Destruction
Recent studies are shedding quite a different light on the way in which innate resistance, as an integral part of inflammation, is participating in oncogenesis and tumor surveillance. For a long time, innate resistance has been considered a primitive non-specific form of resistance to infections eclipsed by the potent and specific acquired immunity of higher organisms. More recently, it has been recognized that innate resistance is not only the first line of defense against infections but it sets the stage and it is necessary for the development of adaptive immunity. It is now becoming evident, however, that the processes that the organisms use for resistance to infections are derived and shared with the mechanisms essential for tissue homeostasis and morphogenesis. Innate resistance is mediated not only by specialized cells but most stromal and parenchyma cells participate in the process and they may express and utilize many of the receptors also utilized by "immune cells" with similar signaling and physiological responses. Similarly, in cancer biology, it is becoming manifest that what used to be considered the defensive mechanisms of innate resistance and inflammation are indeed manifestations of tissue homeostasis and control of cellular proliferation that have many pleiotropic effects on carcinogenesis and tumor progression and dissemination. The interaction of the inflammatory mediators and effector cells with carcinogenesis and tumor progression is complicated and results in effects that either favor or impede tumor progression. The simple concept that early inflammation is necessary for carcinogenesis whereas inflammatory and immune response would prevent, when successful, tumor progression has being replaced by a more subtle understanding that the degree of inflammation and the type of inflammatory/immune response are responsible for tilting the balance between tumor progression and regression. The different investigators of the Cancer and Inflammation Program (CIP), also in collaboration with many investigators focusing in carcinogenesis and tumor biology, both in Bethesda and in Frederick, will be investigating many aspects of the complex cross-talk between inflammation and cancer.
In my own group and in collaboration with the other investigators in the CIP, I plan to pursue a scientific program both in the mouse and in humans on the interface between inflammation, natural resistance and adaptive immunity with a focus on:
- The molecular and cellular mechanisms regulating the activity of dendritic cell subsets, particularly the type I Interferon-producing plasmacytoid dendritic cells as well as conventional dendritic cells and their cross-activating interaction with other inflammatory cell types, natural killer (NK) cells, and T cells.
- The role of plasmacytoid dendritic cells in the regulation of immune response and tolerance in experimental models of cancer, autoimmunity, and infections.
- The study of the molecular, structural and signaling aspects of receptors recognizing pathogens, particularly Toll-like receptors, cytoplasmic NOD and RIG-I-like receptors, and other surface receptor and their synergism/antagonism in the regulation of the inflammatory response.
- The role of cytokines (including IL-12 family, type I and II interferons, interleukin-10) and dendritic cells in regulating the early innate response to infections and cancer and the deviation of the adaptive response for the development of preventive (vaccines) and prophylactic treatments for cancer and infectious diseases.
- The study of the immunosuppressive tumor environment resulting in alternate activation of macrophages and myeloid cells and paralysis of dendritic cells, with an emphasis on the role of IL-10 and STAT3 activation; the reversion of the immunosuppressive environment will be combined to activation of innate resistance or modulation of the inflammatory response for anti-tumor therapy.
- The role of various inflammation-related gene products (tumor necrosis factor, IL-12, IL-23, IL-27, IL-10, IL-17, IL-22, Toll-like receptors and their signaling molecules) in carcinogenesis utilizing various genetic or chemical models of colon and skin carcinogenesis.
Stewart CA, Metheny H, Iida N, Smith L, Hanson M, Steinhagen F, Leighty RM, Roers A, Karp CL, Müller W, Trinchieri G. Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J Clin Invest. 2013;123(11):4859-74.
Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967-70.
Cataisson C, Salcedo R, Hakim S, Moffitt BA, Wright L, Yi M, Stephens R, Dai RM, Lyakh L, Schenten D, Yuspa HS, Trinchieri G. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. J Exp Med. 2012;209(9):1689-702.
Goldszmid RS, Caspar P, Rivollier A, White S, Dzutsev A, Hieny S, Kelsall B, Trinchieri G, Sher A. NK cell-derived interferon-γ orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection. Immunity. 2012;36(6):1047-59.
Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, Wang E, Ma W, Haines D, O'hUigin C, Marincola FM, Trinchieri G. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med. 2010;207(8):1625-36.
Related Scientific Focus Areas
Microbiology and Infectious Diseases
This page was last updated on July 27th, 2017