Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.
T-bet (Tbx21), a T-box transcription factor, has been previously identified as a master regulator of type 1 T cell polarization. We have also recently shown that the genetic engineering of human dendritic cells (DCs) to express human T-bet cDNA yields type 1-polarizing APCs in vitro (1). In the present study, murine CD11c(+) DCs were transduced with a recombinant adenovirus encoding full-length murine T-bets (DC.mTbets) and analyzed for their immunomodulatory functions in vitro and in vivo. Within the range of markers analyzed, DC.mTbets exhibited a control DC phenotype and were indistinguishable from control DCs in their ability to promote allogenic T cell proliferation in MLR in vitro. However, DC.mTbets were superior to control DCs in promoting Th1 and Tc1 responses in vitro via a mechanism requiring DC-T cell interaction or the close proximity of these two cell types and that can only partially be explained by the action of DC-elaborated IL-12p70. When injected into day 7 s.c. CMS4 sarcoma lesions growing in syngenic BALB/c mice, DC.mTbets dramatically slowed tumor progression (versus control DCs) and extended overall survival via a mechanism dependent on both CD4(+) and CD8(+) T cells and, to a lesser extent, asialoGM1(+) NK cells. DC.mTbet-based therapy also promoted superior tumor-specific Tc1 responses in the spleens and tumor-draining lymph nodes of treated animals, and within the tumor microenvironment it inhibited the accumulation of CD11b(+)Gr1(+) myeloid-derived suppressor cells and normalized CD31(+) vascular structures. These findings support the potential translational utility of DC.Tbets as a therapeutic modality in the cancer setting.
Qu
Yanyan
Y
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Chen
Lu
L
Pardee
Angela D
AD
Taylor
Jennifer L
JL
Wesa
Amy K
AK
Storkus
Walter J
WJ
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005818:Genetic Engineering / Q000379:methods*; D006183:H-2 Antigens / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016130:Immunophenotyping; D015552:Injections, Intralesional / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000401:mortality / Q000628:therapy* / Q000821:virology; D020825:T-Box Domain Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic
D006183:H-2 Antigens; C068318:H-2E(k) antigen; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse