Toll like receptors (TLRs) are key sensor of microbes and are expressed on sentinel cells of the immune system. TLRs agonists are potent activators of innate immune responses, activating antigen presenting cells and promoting adaptive immune response. Their use as adjuvants to reinforce the immune response against tumors is among the first and oldest strategies used in anticancer immunity, even before these receptors were described.
Recently, functional TLRs have been shown to be expressed in numerous cancer cells, but their significance has only recently begun to be explored. Our lab is interested in understanding the possible role that TLR4 could be playing in a sterile environment, like tumors. We have reported the consequences of activating TLR4, the receptor for bacterial lipopolisaccharide in tumor cells in different animal models of cance.
We have observed that the activation of TLR4 in tumor cell lines in vitro inhibits the tumor outgrowth in vivo and thatthis effect is not due to a change on the proliferation/apoptosis balance of the tumor cells. We also showed that the in vivo inhibition of tumor growth depends exclusively on TLR4 present on tumor cell themselves and not on antigen presenting cells from the host, using host mice deficient for TLR4 (TLR4 lps-del).
Preliminary data indicates that the T cell compartment is somehow involved in the described phenomenon since the inhibitory effect observed is not seen in athymic nude mice and the phenotype and function of tumor infiltrating lymphocytes purified from tumors induced by TLR4-activated cells is also modified.
We hypothesize that TLR4 signaling in tumor cells in vitro induces the expression of proinflammatory mediators, which could dramatically alter the maturation state of dendritic cells present at the site of inoculation, switching the type of immune response elicited against the tumor.
Our goal is to understand the cellular and molecular mechanisms involved in this phenomenom with the idea of opening up new avenues for understanding the role of TLR4 on tumor cells and for identifying potential new therapy strategies for cancer.
Matsumoto I, M Maccioni, Lee DM, Maurice M, Simmons B, Brenner M, Mathis D, Benoist C.
“How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease”.
Nat Immunol. 3:360-365. 2002
M Maccioni, G. Zeder-Lutz, H Huang, C. Ebel, P. Gerber, J. Hergueux, P. Marchal, V.Duchatelle, C.Degott, M. van Regenmortel, C.Benoist, D. Mathis. “Arthritogenic Monoclonal Antibodies from K/BxN Mice ”. J. Exp. Med 8 : 1071–1077. 2002
P.H.H. Lopez, R.D. Lardone, F.J. Irazoqui, M. Maccioni , G.A. Nores
R.D.Motrich, M Maccioni, R.Molina, A. Tissera, J.Olmedo, C.M.Riera and V.E. Rivero. “Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens. “
Human Reprod 20:2567-72. 2005
R.D. Motrich, M Maccioni, R. Molina, A.Tissera, J.Olmedo, C. M. Riera and V.E.Rivero. “Presence of INFg-secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients”
Clin Immunol. 116:149-57. 2005
G Gatti, V Rivero, R D Motrich and M. Maccioni.
“Prostate epithelial cells can act as early sensors of infection by up--regulating TLR4 expression and pro-inflammatory mediators upon LPS stimulation.”
J Leuko Biol,79: 989-98. 2006.
RD. Motrich , Maccioni M , AA. Ponce , GA. Gatti , JP. Mackern Oberti JP , V E. Rivero
“Pathogenic consequences in semen quality of an autoimmune response against the prostate gland: from animal models to human disease, J Immunol, 177: 957-67. 2006
Mackern-Oberti JP, Maccioni M, Cuffini C, Gatti G, Rivero VE
Susceptibility of prostate epithelial cells to Chlamydia muridarum infection and their role in innate immunity by recruitment of intracellular Toll-like receptors 4 and 2 and MyD88 to the inclusion.
Infect Immun. 74(12):6973-81, 2006
Correa SG, Maccioni M, Rivero VE, Iribarren P, Sotomayor CE, Riera CM.
Cytokines and the immune-neuroendocrine network: What did we learn from infection and autoimmunity? Cytokine Growth Factor Rev. 2007 18:125-34.
V.E. Rivero, R.D. Motrich, M. Maccioni and C.M. Riera
“Autoimmune Etiology in Chronic Prostatitis Syndrome: An advance in the understanding of this pathology” Crit Rev Immunol. 2007;27(1):33-46
Virginia Andreani, Gerardo Gatti, Lucio Simonella, Virginia Rivero and M Maccioni
Activation of TLR4 on tumor cells in vitro inhibits further tumor growth in vivo. Cancer Research 2007; 67 (21):10519-27