SOCS1 restricts dendritic cells' ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling

Evel-Kabler, Kevin; Song, Xiao-Tong; Aldrich, Melissa; Huang, Xue F.; Chen, Si-Yi
January 2006
Journal of Clinical Investigation;Jan2006, Vol. 116 Issue 1, p90
Academic Journal
journal article
DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that self tolerance at the host level is still maintained in the vaccinated hosts. This study in mice reveals a novel regulatory mechanism for the control of self tolerance at the host level by DCs through the restriction of positive cytokine feedback loops by cytokine signaling inhibitor SOCS1. The study further finds the requirement of persistent antigen presentation by DCs for inducing pathological autoimmune responses against normal tissues and tumor, which can be achieved by silencing SOCS1 to unleash the unbridled signaling of IL-12 and the downstream cytokine cascade. However, the use of higher-affinity self peptides, enhancement of DC maturation, and persistent stimulation with cytokines or TLR agonists fail to break tolerance and induce pathological antitumor immunity. Thus, this study indicates the necessity of inhibiting SOCS1, an antigen presentation attenuator, to break self tolerance and induce effective antitumor responses.


Related Articles

  • FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. Watkins, Stephanie K.; Ziqiang Zhu; Riboldi, Elena; Shafer-Weaver, Kim A.; Stagliano, Katherine E. R.; Sklavos, Martha M.; Ambs, Stefan; Yagita, Hideo; Hurwitz, Arthur A.; Zhu, Ziqiang // Journal of Clinical Investigation;Apr2011, Vol. 121 Issue 4, p1361 

    The limited success of cancer immunotherapy is often attributed to the loss of antigen-specific T cell function in situ. However, the mechanism for this loss of function is unknown. In this study, we describe a population of tumor-associated DCs (TADCs) in both human and mouse prostate cancer...

  • Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma. Olvedy, Michael; Tisserand, Julie C.; Luciani, Flavie; Boeckx, Bram; Wouters, Jasper; Lopez, Sophie; Rambow, Florian; Aibar, Sara; Thienpont, Bernard; Barra, Jasmine; Köhler, Corinna; Radaelli, Enrico; Tartare-Deckert, Sophie; Aerts, Stein; Dubreuil, Patrice; van den Oord, Joost J.; Lambrechts, Diether; De Sepulveda, Paulo; Marine, Jean-Christophe // Journal of Clinical Investigation;Jun2017, Vol. 127 Issue 6, p2310 

    Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By...

  • IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. Fisher, Daniel T.; Qing Chen; Skitzki, Joseph J.; Muhitch, Jason B.; Lei Zhou; Appenheimer, Michelle M.; Vardam, Trupti D.; Weis, Emily L.; Passanese, Jessica; Wan-Chao Wang; Gollnick, Sandra O.; Dewhirst, Mark W.; Rose-John, Stefan; Repasky, Elizabeth A.; Baumann, Heinz; Evans, Sharon S.; Chen, Qing; Zhou, Lei; Wang, Wan-Chao // Journal of Clinical Investigation;Oct2011, Vol. 121 Issue 10, p3846 

    Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in...

  • Glycolipid antigen induces long-term natural killer T cell anergy in mice. Parekh, Vrajesh V.; Wilson, Michael T.; Olivares-Villagómez, Danyvid; Singh, Avneesh K.; Lan Wu; Chyung-Ru Wang; Joyce, Sebastian; van Kaer, Luc; Olivares-Villagómez, Danyvid; Wu, Lan; Wang, Chyung-Ru // Journal of Clinical Investigation;Sep2005, Vol. 115 Issue 9, p2572 

    Natural killer T (NKT) cells recognize glycolipid antigens presented by the MHC class I-related glycoprotein CD1d. The in vivo dynamics of the NKT cell population in response to glycolipid activation remain poorly understood. Here, we show that a single administration of the synthetic glycolipid...

  • The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Scuto, A.; Krejci, P.; Popplewell, L.; Wu, J.; Kujawski, M.; Kowolik, C.; Xin, H.; Chen, L.; Wang, Y.; Kretzner, L.; Yu, H.; Wilcox, W. R.; Yen, Y.; Forman, S.; Jove, R. // Leukemia (08876924);Mar2011, Vol. 25 Issue 3, p538 

    IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived...

  • Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. Babitt, Jodie L.; Huang, Franklin W.; Yin Xia; Sidis, Yisrael; Andrews, Nancy C.; Lin, Herbert Y.; Xia, Yin // Journal of Clinical Investigation;Jul2007, Vol. 117 Issue 7, p1933 

    Systemic iron balance is regulated by hepcidin, a peptide hormone secreted by the liver. By decreasing cell surface expression of the iron exporter ferroportin, hepcidin decreases iron absorption from the intestine and iron release from reticuloendothelial stores. Hepcidin excess has been...

  • Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice. Lerner, Immanuel; Hermano, Esther; Zcharia, Eyal; Rodkin, Dina; Bulvik, Raanan; Doviner, Victoria; Rubinstein, Ariel M.; Ishai-Michaeli, Rivka; Atzmon, Ruth; Sherman, Yoav; Meirovitz, Amichay; Peretz, Tamar; Vlodavsky, Israel; Elkin, Michael // Journal of Clinical Investigation;May2011, Vol. 121 Issue 5, p1709 

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the...

  • FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. Kamagate, Adama; Shen Qu; Perdomo, German; Dongming Su; Dae Hyun Kim; Slusher, Sandra; Meseck, Marcia; Dong, H. Henry; Qu, Shen; Su, Dongming; Kim, Dae Hyun // Journal of Clinical Investigation;Jun2008, Vol. 118 Issue 6, p2347 

    Excessive production of triglyceride-rich VLDL is attributable to hypertriglyceridemia. VLDL production is facilitated by microsomal triglyceride transfer protein (MTP) in a rate-limiting step that is regulated by insulin. To characterize the underlying mechanism, we studied hepatic MTP...

  • The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Hussain, S.; Foreman, O.; Perkins, S. L.; Witzig, T. E.; Miles, R. R.; van Deursen, J.; Galardy, P. J. // Leukemia (08876924);Sep2010, Vol. 24 Issue 9, p1641 

    De-ubiquitinating enzymes (DUBs) can reverse the modifications catalyzed by ubiquitin ligases and as such are believed to be important regulators of a variety of cellular processes. Several members of this protein family have been associated with human cancers; however, there is little evidence...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics