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• W2004253170 abstract "We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 complementary DNA (cDNA) would yield improved antitumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8+ T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translation use of combined Tbet and IL-12p70 gene therapy in the cancer setting. We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 complementary DNA (cDNA) would yield improved antitumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8+ T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translation use of combined Tbet and IL-12p70 gene therapy in the cancer setting. The use of dendritic cells (DC) as therapeutic agents and/or vaccine components has received profound attention over the past 15 years, with numerous clinical trials validating the immunogenicity of these cells.1Palucka K Ueno H Banchereau J Recent developments in cancer vaccines.J Immunol. 2011; 186: 1325-1331Crossref PubMed Scopus (149) Google Scholar,2Kalinski P Dendritic cells in immunotherapy of established cancer: Roles of signals 1, 2, 3 and 4.Curr Opin Investig Drugs. 2009; 10: 526-535PubMed Google Scholar,3Gilboa E DC-based cancer vaccines.J Clin Invest. 2007; 117: 1195-1203Crossref PubMed Scopus (472) Google Scholar Although objective responses have been observed in a minority of cancer patients treated with DC-based immunotherapy,4Jandus C Speiser D Romero P Recent advances and hurdles in melanoma immunotherapy.Pigment Cell Melanoma Res. 2009; 22: 711-723Crossref PubMed Scopus (39) Google Scholar,5Vujanovic L Butterfield LH Melanoma cancer vaccines and anti-tumor T cell responses.J Cell Biochem. 2007; 102: 301-310Crossref PubMed Scopus (31) Google Scholar such responders provide hope that the application of ex vivo generated DC or development of means through which to activate the increasingly complex range of DC subsets in vivo may lead to improved clinical efficacy. Since type-1 T cell responses (particularly CD8+ T cells; i.e., Tc1) have been associated with most beneficial outcomes as a consequence of immunotherapeutic intervention,6Bose A Taylor JL Alber S Watkins SC Garcia JA Rini BI et al.Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination.Int J Cancer. 2011; 129: 2158-2170Crossref PubMed Scopus (116) Google Scholar,7Dobrzanski MJ Reome JB Dutton RW Therapeutic effects of tumor-reactive type 1 and type 2 CD8+ T cell subpopulations in established pulmonary metastases.J Immunol. 1999; 162: 6671-6680PubMed Google Scholar,8Dudley ME Gross CA Langhan MM Garcia MR Sherry RM Yang JC et al.CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma.Clin Cancer Res. 2010; 16: 6122-6131Crossref PubMed Scopus (242) Google Scholar many including ourselves, have focused on ways to condition patient DC to exert a predictable type-1 functional polarization potential on responder T cells.9Kapsenberg ML Hilkens CM Wierenga EA Kalinski P The paradigm of type 1 and type 2 antigen-presenting cells. Implications for atopic allergy.Clin Exp Allergy. 1999; 29: 33-36Crossref PubMed Scopus (120) Google Scholar,10Mailliard RB Wankowicz-Kalinska A Cai Q Wesa A Hilkens CM Kapsenberg ML et al.alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity.Cancer Res. 2004; 64: 5934-5937Crossref PubMed Scopus (422) Google Scholar,11Tada H Aiba S Shibata K Ohteki T Takada H Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells.Infect Immun. 2005; 73: 7967-7976Crossref PubMed Scopus (297) Google Scholar,12Napolitani G Rinaldi A Bertoni F Sallusto F Lanzavecchia A Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.Nat Immunol. 2005; 6: 769-776Crossref PubMed Scopus (971) Google Scholar In addition to employing culture conditions that incorporate pro-inflammatory cytokines or toll-like receptor agonists (in order to largely bolster DC production of IL-12p70 and/or diminished IL10 production), one may genetically engineer DC to attain so-called “DC1” functional status.10Mailliard RB Wankowicz-Kalinska A Cai Q Wesa A Hilkens CM Kapsenberg ML et al.alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity.Cancer Res. 2004; 64: 5934-5937Crossref PubMed Scopus (422) Google Scholar,11Tada H Aiba S Shibata K Ohteki T Takada H Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells.Infect Immun. 2005; 73: 7967-7976Crossref PubMed Scopus (297) Google Scholar,12Napolitani G Rinaldi A Bertoni F Sallusto F Lanzavecchia A Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.Nat Immunol. 2005; 6: 769-776Crossref PubMed Scopus (971) Google Scholar,13Tatsumi T Huang J Gooding WE Gambotto A Robbins PD Vujanovic NL et al.Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.Cancer Res. 2003; 63: 6378-6386PubMed Google Scholar,14Lipscomb MW Chen L Taylor JL Goldbach C Watkins SC Kalinski P et al.Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.J Immunol. 2009; 183: 7250-7258Crossref PubMed Scopus (28) Google Scholar,15Qu Y Chen L Pardee AD Taylor JL Wesa AK Storkus WJ Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.J Immunol. 2010; 185: 2895-2902Crossref PubMed Scopus (14) Google Scholar,16Yao Y Li W Kaplan MH Chang CH Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells.J Exp Med. 2005; 201: 1899-1903Crossref PubMed Scopus (125) Google Scholar In particular, DC1 engineered to express ectopic IL-12p70 or the T cell transactivator protein TBX21 (aka Tbet) have been shown to serve as effective antigen presenting cells (APC) for the promotion of potent Tc1 responses in vitro and in vivo that are competent to mediate tumor rejection.13Tatsumi T Huang J Gooding WE Gambotto A Robbins PD Vujanovic NL et al.Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.Cancer Res. 2003; 63: 6378-6386PubMed Google Scholar,14Lipscomb MW Chen L Taylor JL Goldbach C Watkins SC Kalinski P et al.Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.J Immunol. 2009; 183: 7250-7258Crossref PubMed Scopus (28) Google Scholar,15Qu Y Chen L Pardee AD Taylor JL Wesa AK Storkus WJ Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.J Immunol. 2010; 185: 2895-2902Crossref PubMed Scopus (14) Google Scholar Interestingly, DC1 engineered to express Tbet (i.e., DC.Tbet) appear capable of preferentially activating type-1 T cell responses from naive T cell precursors via a mechanism that depends minimally on the action of IL-12p70.14Lipscomb MW Chen L Taylor JL Goldbach C Watkins SC Kalinski P et al.Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.J Immunol. 2009; 183: 7250-7258Crossref PubMed Scopus (28) Google Scholar,15Qu Y Chen L Pardee AD Taylor JL Wesa AK Storkus WJ Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.J Immunol. 2010; 185: 2895-2902Crossref PubMed Scopus (14) Google Scholar Given the lack of major operational overlap between DC1-associated IL-12p70 and Tbet in supporting type-1 immunity from naive responder T cells, we hypothesized that the engineering of DC to express high levels of both proteins might yield an “uber-DC1” capable of cross-priming a superior level of protective Tc1-mediated immunity in the cancer setting. We directly investigated this possibility using CMS4 (H-2d) sarcoma or B16 (H-2b) melanoma in syngenic mice applying genetically altered DC1 either as a therapeutic agent directly injected into established tumor lesions or as a vaccine adjuvant injected distal to tumor sites. In both formats, DC.Tbet/IL12 were determined to activate greater systemic levels of antitumor Tc1 in association with improved treatment outcome when compared with all formats of control DC evaluated. These data suggest that DC.Tbet/IL12 or alternate conditional means to promote higher levels of Tbet and IL-12p70 in therapeutic DC1 may lead to enhanced rates of objective clinical response in patients with cancer. One million control or genetically engineered DC were injected directly into subcutaneous (s.c.) CMS4 sarcoma tumors established for 7 days in syngenic BALB/c mice. An identical treatment was provided to each cohort of animals 1 week later (i.e., day 14 post-tumor inoculation). As shown in Figure 1a, while mice treated with DC infected with Ad.ψ5 (i.e., DC.ψ5) displayed progressive tumor growth that was indistinguishable from untreated mice, animals treated with DC.Tbet, DC.IL12 or DC.Tbet/IL12 exhibited either slowed tumor progression (for DC.Tbet and DC.IL12) or regression (for DC.Tbet/IL12). Mice treated with DC.Tbet/IL12 exhibited a statistically meaningful benefit over DC.Tbet or DC.IL12 monotherapy (i.e., P < 0.05) after day 25 (Figure 1a), which was also reflected in extended overall survival (Figure 1b; DC.Tbet/IL12 versus DC.Tbet (P = 0.006), DC.IL12 (P = 0.029) or DC.ψ5 (P < 0.00007), with P = 0.009 for DC.Tbet versus DC.ψ5 and P = 0.003 for DC.IL12 versus DC.ψ5). Splenic CD8+ T cells were harvested from all cohorts on day 21 post-tumor inoculation and analyzed for reactivity against syngenic DC alone or DC pulsed with peptides extracted by mild acid elution17Komita H Zhao X Taylor JL Sparvero LJ Amoscato AA Alber S et al.CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.Cancer Res. 2008; 68: 8076-8084Crossref PubMed Scopus (24) Google Scholar from enzymatically digested CMS4 tumors by interferon-γ (IFN-γ) enzyme-linked immunosorbent assay. Data provided in Figure 2 suggests that the profile of type-1 CD8+ T cell reactivity against peptides contained in individual high-performance liquid chromatography (HPLC) fractions differs dramatically between the various treatment cohorts, with untreated or DC.ψ5-treated animals exhibiting a general lack of response to in vivo presented peptides, while mice treated with DC.Tbet, DC.IL12 or DC.Tbet/IL12 demonstrate response to a range of peptide-containing fractions. In particular, Tc1 cells isolated from mice treated with DC.Tbet/IL12 displayed the strongest and most complex pattern of peptide recognition among all cohorts, with such recognition proving to be H-2d class I-restricted (Figure 2). Although the data provided in Figure 2 suggest that the systemic CD8+ T cell repertoire becomes educated to react against antigens expressed within the tumor microenvironment, particularly after treatment with DC.Tbet/IL12, the identity of specific peptide sequences and the tumor/stromal cells presenting such peptides remained unknown. To determine relevant cellular targets, we analyzed immune CD8+ T cell reactivity against flow cytometry-sorted CD31neg platelet-derived growth factor receptor-β (PDGFRβ)+ pericytes and CD31+PDGFRβneg vascular endothelial cells (VEC) (isolated from the tumors or tumor-uninvolved kidneys of day 21 untreated animals; Figure 3a), in addition to CMS4 tumor cells themselves. The absence of tumor cells in the sorted pericyte and VEC populations was confirmed by reverse transcription-PCR analysis for the tumor-associated MuLV gp70 env gene product (Figure 3b). As depicted in Figure 3c, Tc1 cells isolated from mice treated with DC.Tbet, DC.IL12 or DC.Tbet/IL12 recognized tumor cells and pericytes/VEC purified from the tumors, but not the kidneys of tumor-bearing animals to a comparable degree. The superior antitumor impact of such T cells in the DC.Tbet/IL12 treatment cohort may instead reflect the dramatically increased recruitment of CD8+ T cells into the CMS4 tumor microenvironment (Figure 4a; P < 0.05 versus all other cohorts).Figure 4DC.Tbet/IL12 gene therapy leads to superior infiltration of CD8+ T cells and production of CXCR3 ligand chemokines in the tumor microenvironment. Day 21 tumor and kidney (from the same tumor-bearing animal) sections harvested from mice treated as outlined in Figure 1 were analyzed for expression of (a) CD8 or (b) CD31 and the chemokines CXCL9/Mig and CXCL10/IP-10 (for tumor) by fluorescence microscopy as described in Materials and Methods. For each section (right hand subpanels), 10 high-power fields (HPF; ×40) were quantified for the number of chemokine+ cells and results reported as the mean ± SD per HPF. *P < 0.05 versus untreated or Dc.ψ5; **P < 0.05 versus all other cohorts. Data are from one representative experiment of three performed. DAPI, 4′,6-diamidino-2-phenylindole; DC, dendritic cell; IL, interleukin; Tbet, T-box expressed in T cells.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Since protective Tc1 are recruited into tumors by CXCR3 ligand chemokines,6Bose A Taylor JL Alber S Watkins SC Garcia JA Rini BI et al.Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination.Int J Cancer. 2011; 129: 2158-2170Crossref PubMed Scopus (116) Google Scholar we next analyzed day 21 tumor sections for perivascular expression of CXCL9/Mig and CXCL10/IP-10 by immunofluorescence microscopy (Figure 4b). We observed that the frequency of cells expressing/producing these chemokines within the tumor was increased (versus untreated or DC.ψ5-treated conditions) after treatment with DC.Tbet, DC.IL12 or DC.Tbet/IL12, with the greatest increase associated with DC.Tbet/IL12-based therapy (P < 0.05 versus all cohorts for both chemokines). To determine whether DC.Tbet/IL12 engineered cells would also represent a preferred “adjuvant” in therapeutic vaccines, we treated CMS4 bearing BALB/c mice or B16-bearing C57BL/6 mice with syngenic DC/peptide (hemoglobin-β (HBB)33–42 for CMS4; (ref. 17Komita H Zhao X Taylor JL Sparvero LJ Amoscato AA Alber S et al.CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth.Cancer Res. 2008; 68: 8076-8084Crossref PubMed Scopus (24) Google Scholar) or tyrosinase-related protein 2 (TRP2)180–188 for B16 (ref. 18Tüting T Gambotto A DeLeo A Lotze MT Robbins PD Storkus WJ Induction of tumor antigen-specific immunity using plasmid DNA immunization in mice.Cancer Gene Ther. 1999; 6: 73-80Crossref PubMed Scopus (74) Google Scholar))-based vaccines on days 7 and 14 post-tumor inoculation. Although DC.ψ5/peptide vaccines failed to alter the progressive growth and demise of tumor-bearing animals in either model system, vaccines based on peptide-loaded DC.Tbet, DC.IL12 or DC.Tbet/IL12 either dramatically slowed tumor growth or they promoted disease regression (Figure 5a,c). Such antitumor impact was directly associated with the degree of antigen-specific Tc1 reactivity detected in the spleens of these treated animals (Figure 5b,d). Although we were unable to discern a treatment benefit advantage for the DC.Tbet/IL12/peptide vaccine versus the DC.IL12/peptide vaccine in the CMS4 model (Figure 5a; presumably due to the very strong antitumor action of the DC.IL12-based treatment), we noted a statistical advantage for the combined gene vaccine (versus all other treatment cohorts) for tumor growth suppression of B16 melanoma (Figure 5c) and for specific Tc1 activation in both models (Figure 5b,d). The major finding in the current report is that ectopic (over)expression of both Tbet and IL-12p70 complementary DNA (cDNA) in DC conveys a superior level of cross-priming potential for protective type-1 CD8+ T cells in the tumor-bearing host. This enhanced potential was displayed in therapeutic models in which genetically engineered DC were injected directly into established s.c. tumors or at a site distal to tumor lesions after being pulsed ex vivo with a relevant tumor-associated antigenic peptide (i.e., a vaccine formulation). Provision of DC.Tbet/IL12 into the tumor site allowed these APC to acquire not only tumor, but also stromal (i.e., pericytes and VEC) antigens in situ, leading to systemic activation of Tc1 reactive against tumor cells as well as tumor-associated pericytes and VEC. Indeed, in bilateral established tumor models, i.t. delivery of DC.Tbet/IL12 into one tumor site resulted in dramatically suppressed tumor growth of both the treated and untreated lesions (Supplementary Figure S1). Although DC.Tbet and DC.IL12 also exhibit the biologic potential to activate a protective CD8+ T cell repertoire, the magnitude and diversity of specificity (based on the pattern of recognition of HPLC fractionated peptides isolated from resected tumor/stromal cell populations) displayed by the DC.Tbet/IL12-primed Tc1 repertoire was greater than that associated with the DC.Tbet- or DC.IL12-based treatments. Importantly, from a safety perspective, the H-2d class I-restricted CD8+ T effector cells promoted by i.t. administration of DC.Tbet/IL12 failed to recognize pericytes or VEC flow-sorted from the tumor-uninvolved kidneys of treated mice. Interestingly, the superior efficacy of i.t. DC.Tbet/IL12 therapy was also associated with higher levels of CD8+ T cell recruitment into tumor lesions, likely the result of locoregional production of CXCR3 chemokines such as CXCL9/Mig and/or CXCL10/IP-10 which were profoundly enhanced in their expression in DC.Tbet/IL12-treated lesions. Since the majority of DC injected into tumors fail to leave, and may die within, the tumor microenvironment,13Tatsumi T Huang J Gooding WE Gambotto A Robbins PD Vujanovic NL et al.Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.Cancer Res. 2003; 63: 6378-6386PubMed Google Scholar,19Feijoó E Alfaro C Mazzolini G Serra P Peñuelas I Arina A et al.Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8.Int J Cancer. 2005; 116: 275-281Crossref PubMed Scopus (96) Google Scholar these results are consistent with the ability of i.t.-delivered DC.Tbet/IL12 to condition both the tumor and secondary lymphoid microenvironments in a manner conducive to therapeutic Tc1 differentiation in the periphery and the subsequent delivery of circulating T effector cells into tumor sites. Based on our previous report that IL12 gene insertion into DC extends their lifespan within the tumor microenvironment,13Tatsumi T Huang J Gooding WE Gambotto A Robbins PD Vujanovic NL et al.Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity.Cancer Res. 2003; 63: 6378-6386PubMed Google Scholar we would expect that DC.Tbet/IL12 would also live longer and sustain their protective functionality within this hostile niche. Importantly, even when not asked to take up environmental antigens or to condition the tumor microenvironment, DC.Tbet/IL12 consistently served as a superior “biologic adjuvant” when used in therapeutic peptide-based (synthetic and/or natural acid-eluted; Figure 5 and Supplementary Figure S2) vaccine formulations injected distal to tumors. Interestingly, therapeutic vaccines based on a mixture of synthetic TRP2180–188 peptide and natural tumor-derived peptides appeared to provide somewhat stronger anti-B16 melanoma benefit to treated animals when compared to vaccines formulated as either synthetic or natural peptides (Supplementary Figure S2). This could result from: (i) complementation in the largely nonoverlapping responder Tc1 repertoires directed against each set of peptides, and/or (ii) the influence of type-1 helper (Tc1 or Th1) responses that bolster Tc1 reactivity against both sets of target epitopes. These possibilities will be further investigated in prospective studies. The direct mechanism of action associated with the DC.Tbet/IL12 treatment benefit remains unknown. While intrinsic Tbet expression appears crucial to the ability of DC to drive protective or pathologic type-1 T cell responses,20Lugo-Villarino G Maldonado-Lopez R Possemato R Penaranda C Glimcher LH T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells.Proc Natl Acad Sci USA. 2003; 100: 7749-7754Crossref PubMed Scopus (218) Google Scholar,21Esensten JH Lee MR Glimcher LH Bluestone JA T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function.J Immunol. 2009; 183: 75-82Crossref PubMed Scopus (58) Google Scholar,22Wang J Fathman JW Lugo-Villarino G Scimone L von Andrian U Dorfman DM et al.Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells.J Clin Invest. 2006; 116: 414-421Crossref PubMed Scopus (102) Google Scholar,23Heckman KL Radhakrishnan S Peikert T Iijima K McGregor HC Bell MP et al.T-bet expression by dendritic cells is required for the repolarization of allergic airway inflammation.Eur J Immunol. 2008; 38: 2464-2474Crossref PubMed Scopus (10) Google Scholar,24Lugo-Villarino G Ito S Klinman DM Glimcher LH The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells.Proc Natl Acad Sci USA. 2005; 102: 13248-13253Crossref PubMed Scopus (51) Google Scholar it remains unclear how ectopic overexpression of Tbet confers improved type-1 polarizing potential on these APC. In our previous reports,14Lipscomb MW Chen L Taylor JL Goldbach C Watkins SC Kalinski P et al.Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.J Immunol. 2009; 183: 7250-7258Crossref PubMed Scopus (28) Google Scholar,15Qu Y Chen L Pardee AD Taylor JL Wesa AK Storkus WJ Intralesional delivery of dendritic cells engineered to express T-bet promotes protective type 1 immunity and the normalization of the tumor microenvironment.J Immunol. 2010; 185: 2895-2902Crossref PubMed Scopus (14) Google Scholar we observed that DC.Tbet were efficient activators of type-1 T cell responses from naive T cell precursors and that such activation required close DC–T cell proximity, but not the “usual suspect” pro-inflammatory cytokines, including DC-elaborated IL-12p70, IL-23, IL-27 or IFN-γ itself. Indeed, our pilot data suggest that DC.Tbet developed from IL-12p35−/− mice display comparable antitumor efficacy to wild-type DC.Tbet when injected directly into s.c. tumor lesions (L. Chen, unpublished results). In this context, IL12-independent pathways for type-1 T cell induction have been reported, in which enhanced (IFN-α/β or IL-18; (refs. 25Yu HR Chen RF Hong KC Bong CN Lee WI Kuo HC et al.IL-12-independent Th1 polarization in human mononuclear cells infected with varicella- zoster virus.Eur J Immunol. 2005; 35: 3664-3672Crossref PubMed Scopus (32) Google Scholar,26Cousens LP Peterson R Hsu S Dorner A Altman JD Ahmed R et al.Two roads diverged: interferon alpha/beta- and interleukin 12-mediated pathways in promoting T cell interferon gamma responses during viral infection.J Exp Med. 1999; 189: 1315-1328Crossref PubMed Scopus (251) Google Scholar,27Osaki T Péron JM Cai Q Okamura H Robbins PD Kurimoto M et al.IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL- 12- independent antitumor effects.J Immunol. 1998; 160: 1742-1749PubMed Google Scholar) or decreased (IL-10, (ref. 28Chiaramonte MG Hesse M Cheever AW Wynn TA CpG oligonucleotides can prophylactically immunize against Th2-mediated schistosome egg-induced pathology by an IL-12-independent mechanism.J Immunol. 2000; 164: 973-985Crossref PubMed Scopus (60) Google Scholar)) cytokine production by APC have been suggested as dominant drivers for Th1/Tc1 response bias. Interestingly, CpG ODN adjuvants that require APC expression of Tbet24Lugo-Villarino G Ito S Klinman DM Glimcher LH The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells.Proc Natl Acad Sci USA. 2005; 102: 13248-13253Crossref PubMed Scopus (51) Google Scholar preferentially promote type-1–mediated immunity in an IL12-independent manner via a mechanism involving downregulation of IL-10 production and co-inhibitory molecule expression by DC.24Lugo-Villarino G Ito S Klinman DM Glimcher LH The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells.Proc Natl Acad Sci USA. 2005; 102: 13248-13253Crossref PubMed Scopus (51) Google Scholar,28Chiaramonte MG Hesse M Cheever AW Wynn TA CpG oligonucleotides can prophylactically immunize against Th2-mediated schistosome egg-induced pathology by an IL-12-independent mechanism.J Immunol. 2000; 164: 973-985Crossref PubMed Scopus (60) Google Scholar Alternatively or additionally, LPS-activated murine CD8neg DC have been reported to induce Th1 responses via an IL12-independent mechanism that involves Delta-4 (DLL4)-NOTCH signaling29Skokos D Nussenzweig MC CD8- DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS.J Exp Med. 2007; 204: 1525-1531Crossref PubMed Scopus (145) Google Scholar and DEC-205+ DC foster Th1 responses via a CD70-CD27-dependent pathway that does not require IL-12p70.30Soares H Waechter H Glaichenhaus N Mougneau E Yagita H Mizenina O et al.A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo.J Exp Med. 2007; 204: 1095-1106Crossref PubMed Scopus (247) Google Scholar Although our previous in vitro results obtained appear to refute the dominant use of the NOTCH- or CD70-dependent signaling pathways by human DC.Tbet in activating Th1/Tc1 cells from naive responders,14Lipscomb MW Chen L Taylor JL Goldbach C Watkins SC Kalinski P et al.Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.J Immunol. 2009; 183: 7250-7258Crossref PubMed Scopus (28) Google Scholar preliminary gene array analyses suggest that murine DC.Tbet may be coordinately enriched in NOTCH and depleted of IL-10/TGF-β signaling pathway competency (Supplementary Figure S3 and L. Chen, unpublished results). Interestingly, these endpoints may be operationally inter-related since NOTCH-mediated signaling has been reported to suppress p38 mitogen-activated protein kinase (MAPK) activation,31Kondoh K Sunadome K Nishida E Notch signaling suppresses p38 MAPK activity via induction of MKP-1 in myogenesis.J Biol Chem. 2007; 282: 3058-3065Crossref PubMed Scopus (68) Google Scholar and enhanced p38 MAPK activation has been linked with tumor-induced DC dysfunction,32Wang S Yang J Qian J Wezeman M Kwak LW Yi Q Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multipl" @default.
• W2004253170 created "2016-06-24" @default.
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• W2004253170 date "2012-03-01" @default.
• W2004253170 modified "2023-10-01" @default.
• W2004253170 title "Combined Tbet and IL12 Gene Therapy Elicits and Recruits Superior Antitumor Immunity In Vivo" @default.
• W2004253170 cites W1512834386 @default.
• W2004253170 cites W1540648309 @default.
• W2004253170 cites W1561649423 @default.
• W2004253170 cites W1699419672 @default.
• W2004253170 cites W1758585762 @default.
• W2004253170 cites W1852423965 @default.
• W2004253170 cites W1925730260 @default.
• W2004253170 cites W1976358776 @default.
• W2004253170 cites W1979603317 @default.
• W2004253170 cites W1984390981 @default.
• W2004253170 cites W1994310347 @default.
• W2004253170 cites W2004911979 @default.
• W2004253170 cites W2012738471 @default.
• W2004253170 cites W2013155982 @default.
• W2004253170 cites W2019805571 @default.
• W2004253170 cites W2031674055 @default.
• W2004253170 cites W2037425582 @default.
• W2004253170 cites W2045421142 @default.
• W2004253170 cites W2049929103 @default.
• W2004253170 cites W2052997401 @default.
• W2004253170 cites W2063287346 @default.
• W2004253170 cites W2074325144 @default.
• W2004253170 cites W2074664219 @default.
• W2004253170 cites W2076428414 @default.
• W2004253170 cites W2078151312 @default.
• W2004253170 cites W2085865032 @default.
• W2004253170 cites W2098267542 @default.
• W2004253170 cites W2101786076 @default.
• W2004253170 cites W2106841351 @default.
• W2004253170 cites W2116709327 @default.
• W2004253170 cites W2117439988 @default.
• W2004253170 cites W2124254978 @default.
• W2004253170 cites W2128657286 @default.
• W2004253170 cites W2129352244 @default.
• W2004253170 cites W2131874142 @default.
• W2004253170 cites W2149118203 @default.
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