Theme 1: Innate immunity and signaling mechanisms
One reason many current forms of cancer immunotherapy have low clinical response rates is because they fail to activate the innate immune system - a prerequisite for forming long-lasting adaptive immune responses that are necessary to eliminate tumors and prevent their recurrence.
Several CCIR members are investigating the development and function of innate immune cells and receptor-mediated signal transduction pathways leading to expression of cytokines and costimulatory molecules involved in T cell activation and differentiation in order to find ways to enable cancer immunotherapy to activate innate immunity leading to durable anti-tumor T cell responses.
Some highlights from Fiscal Year 2013 include:
- A recent study used unbiased approaches to demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped follicular lymphoma BCRs and also recognized by the Igs of mantle cell lymphoma and multiple myeloma, suggesting that vimentin may play a role in the pathogenesis of multiple B cell malignancies (Cha SC, J Immunol. 2013)
- Findings from a study published in Nature established OTUD7B, a novel deubiquitinase, as a crucial regulator of signal-induced non-canonical NF-κB activation, allowing the authors to propose a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3 (Hu H, Nature, 2013)
- CD13+ bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis (Dondossola E, PNAS. 2013)
Additional Relevant Publications
- Chodaczek G, Papanna V, Zal MA, Zal T. Body-barrier surveillance by epidermal γδ TCRs. Nat Immunol. 2012, 13(3):272-82.
- Li HS, Gelbard A, Martinez GJ, Esashi E, Zhang H, Nguyen-Jackson H, Liu YJ, Overwijk WW, Watowich SS. Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. Blood. 2011, 118(14):3879-89.
- Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol. 2011, 12(10):959-65.
- Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA, Qin J, Cheng G, Liu YJ. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity. 2011, 34(6):866-78.
- Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V, Bover L, Plumas J, Chaperot L, Qin J, Liu YJ. Aspartate-glutamate-alanine- histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc Natl Acad Sci U S A. 2010, 107(34):15181-6.
- Castillo EF, Acero LF, Stonier SW, Zhou D, Schluns KS. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation. Blood. 2010, 116(14):2494-503.
- Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood. 2010, 116(14):2462-71.
- Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood. 2010, 116(2):210-7.
- Nguyen-Jackson H, Panopoulos AD, Zhang H, Li HS, Watowich SS. STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction. Blood. 2010, 115(16):3354-63.
- Arima K, Watanabe N, Hanabuchi S, Chang M, Sun SC, Liu YJ. Distinct signal codes generate dendritic cell functional plasticity. Sci Signal. 2010, Jan 19;3(105):ra4.
- Fontenot D, He H, Hanabuchi S, Nehete PN, Zhang M, Chang M, Nehete B, Wang YH, Wang YH, Ma ZM, Lee HC, Ziegler SF, Courtney AN, Miller CJ, Sun SC, Liu YJ, Sastry KJ. TSLP production by epithelial cells exposed to immunodeficiency virus triggers DC-mediated mucosal infection of CD4+ T cells. Proc Natl Acad Sci U S A. 2009, 106(39):16776-81.
- Chang M, Jin W, Sun SC. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol 2009, 10(10):1089-95.
- Castillo EF, Stonier SW, Frasca L, Schluns KS. Dendritic cells support the in vivo development and maintenance of NK cells via IL-15 trans-presentation. J Immunol. 2009, 183(8):4948-56.
- Cao W, Bover L, Cho M, Hanabuchi S, Bao M, Rosen DB, Wang Y-H,Shaw JL, Du Q, Arai N, Yao Z, Lanier LL, Liu Y-J. Regulation of TLR7/9 Responses in Plasmacytoid Dendritic Cells by BST2 and ILT7 Receptor Interaction. J Exp Med 2009, 206(7):1603-14.
- Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, Homey B, Barrat FJ, Zal T, Gilliet M. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 2009, 206(9): 1983-94.
- Lu N, Wang YH, Wang YH, Arima K, Hanabuchi S, Liu YJ. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med 2009, 206(10): 2111-9.
- Esashi E, Wang YH, Perng O, Qin XF, Liu YJ, Watowich SS. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity. 2008, 28(4):509-20.
- Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A, Imaizumi T, Sun SC. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem. 2008, 283(27):18621-6.