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• W2077632034 abstract "We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8+ T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8+ T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8+ T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response. We have previously shown that for the majority of antigens, adenoviral vaccines expressing the target antigen fused to the MHC associated invariant chain (Ii) induce an accelerated, augmented, and prolonged transgene-specific CD8+ T-cell response. Here we describe a new adenoviral vaccine vector approach where the target antigen fused to Ii is expressed from the adenoviral E1 region and IL-2 is expressed from the E3 region. Immunization of mice with this new vector construct resulted in an augmented primary effector CD8+ T-cell response. Furthermore, in a melanoma model we observed significantly prolonged tumor control in vaccinated wild type (WT) mice. The improved tumor control required antigen-specific cells, since no tumor control was observed, unless the melanoma cells expressed the vaccine targeted antigen. We also tested our new vaccine in immunodeficient (CD80/86 deficient) mice. Following vaccination with the IL-2 expressing construct, these mice were able to raise a delayed but substantial CD8+ T-cell response, and to control melanoma growth nearly as efficaciously as similarly vaccinated WT mice. Taken together, these results demonstrate that current vaccine vectors can be improved and even tailored to meet specific demands: in the context of therapeutic vaccination, the capacity to promote an augmented effector T-cell response. Over time, many strategies to induce potent tumor-specific T-cell responses have been devised. However, most potential cancer vaccines fail to provide convincing results in human patients with advanced disease, thus leaving plenty of room for improvement. Compared to vaccination against pathogens, tumor therapy is extremely demanding as one often has to cope with a pre-established state of immune dysfunction induced by the tumor and its environment.1Gajewski TF Woo SR Zha Y Spaapen R Zheng Y Corrales L et al.Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment.Curr Opin Immunol. 2013; 25: 268-276Crossref PubMed Scopus (314) Google Scholar CD8+ T cells are generally believed to play a key role in tumor control, and, consequently, the induction of a potent tumor-specific CD8+ T-cell response represents a major goal of any tumor vaccine. Replication deficient adenoviruses, particularly of the group C subtype, have been found to be very efficient inducers of potent CD8+ T-cell responses as demonstrated in both mice and primates.2Colloca S Barnes E Folgori A Ammendola V Capone S Cirillo A et al.Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species.Sci Transl Med. 2012; 4: 115ra2Crossref PubMed Scopus (227) Google Scholar Interestingly, in recent studies we showed that a vaccine expressing an exogenous tumor antigen (the glycoprotein of lymphocytic choriomeningitis virus (LCMV GP)) fused to the MHC class II associated Invariant chain (Ii) (Ad5-IiGP) elicits an augmented CD8+ T-cell response.3Holst PJ Sorensen MR Mandrup Jensen CM Orskov C Thomsen AR Christensen JP MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines.J Immunol. 2008; 180: 3339-3346Crossref PubMed Scopus (75) Google Scholar Furthermore, when this vaccine was tested in a tumor model against hard-to-treat GP-expressing melanomas, significantly prolonged tumor control was observed.4Sorensen MR Holst PJ Pircher H Christensen JP Thomsen AR Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control.Eur J Immunol. 2009; 39: 2725-2736Crossref PubMed Scopus (35) Google Scholar Nevertheless, although tumor growth could be dramatically delayed using improved adenoviral vaccines, non-eradicated melanoma cells still tended to rebound, and long-term survival of tumor challenged mice remained unachievable unless additional therapy was provided.5Sorensen MR Holst PJ Steffensen MA Christensen JP Thomsen AR Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model.Vaccine. 2010; 28: 6757-6764Crossref PubMed Scopus (47) Google Scholar The mechanism underlying this consistent tumor re-growth is unknown, but it could theoretically be caused by both immune escape and/or the gradual establishment of an immunosuppressive tumor microenvironment.6Rabinovich GA Gabrilovich D Sotomayor EM Immunosuppressive strategies that are mediated by tumor cells.Annu Rev Immunol. 2007; 25: 267-296Crossref PubMed Scopus (1288) Google Scholar Accordingly, we hypothesized that adenoviral vaccine vectors co-expressing a tumor Ag alongside a cytokine, which promotes effector T-cell differentiation, might increase the antitumor efficacy. Accordingly, we redesigned our Ad5 vector expressing LCMV GP fused to Ii to co-express interleukin-2 (Ad5-IiGP-IL-2). Based on in vitro studies, IL-2 was initially considered a unique T-cell growth factor and a “master cytokine” in relation to T-cell activation.7Gillis S Smith KA Long term culture of tumour-specific cytotoxic T cells.Nature. 1977; 268: 154-156Crossref PubMed Scopus (1124) Google Scholar,8Smith KA Interleukin-2: inception, impact, and implications.Science. 1988; 240: 1169-1176Crossref PubMed Scopus (1900) Google Scholar The role of IL-2 signaling in vivo, on the other hand, has until recently been quite difficult to define.9Bachmann MF Oxenius A Interleukin 2: from immunostimulation to immunoregulation and back again.EMBO Rep. 2007; 8: 1142-1148Crossref PubMed Scopus (176) Google Scholar One reason for this is that besides serving as an immune-enhancer, IL-2 may also promote activation-induced cell death10Lenardo MJ Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis.Nature. 1991; 353: 858-861Crossref PubMed Scopus (957) Google Scholar and exert a positive feed-back on regulatory T cells (Tregs).11Klebb G Autenrieth IB Haber H Gillert E Sadlack B Smith KA et al.Interleukin-2 is indispensable for development of immunological self-tolerance.Clin Immunol Immunopathol. 1996; 81: 282-286Crossref PubMed Scopus (64) Google Scholar,12Papiernik M de Moraes ML Pontoux C Vasseur F Pénit C Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency.Int Immunol. 1998; 10: 371-378Crossref PubMed Scopus (390) Google Scholar However, a growing body of experimental evidence now unequivocally point to a non-redundant role of IL-2 in promoting the differentiation and accumulation of cytolytic effector CD8+ T cells in vivo.13Pipkin ME Sacks JA Cruz-Guilloty F Lichtenheld MG Bevan MJ Rao A Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.Immunity. 2010; 32: 79-90Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar,14Mitchell DM Ravkov EV Williams MA Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8+ effector and memory T cells.J Immunol. 2010; 184: 6719-6730Crossref PubMed Scopus (87) Google Scholar,15Williams MA Tyznik AJ Bevan MJ Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells.Nature. 2006; 441: 890-893Crossref PubMed Scopus (602) Google Scholar,16Bachmann MF Wolint P Walton S Schwarz K Oxenius A Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections.Eur J Immunol. 2007; 37: 1502-1512Crossref PubMed Scopus (151) Google Scholar,17Blattman JN Grayson JM Wherry EJ Kaech SM Smith KA Ahmed R Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo.Nat Med. 2003; 9: 540-547Crossref PubMed Scopus (309) Google Scholar,18Kalia V Sarkar S Subramaniam S Haining WN Smith KA Ahmed R Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo.Immunity. 2010; 32: 91-103Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar,19D'souza WN Schluns KS Masopust D Lefrançois L Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T cell responses.J Immunol. 2002; 168: 5566-5572Crossref PubMed Scopus (102) Google Scholar,20D'souza WN Lefrançois L IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion.J Immunol. 2003; 171: 5727-5735Crossref PubMed Scopus (186) Google Scholar,21Cheng LE Greenberg PD Selective delivery of augmented IL-2 receptor signals to responding CD8+ T cells increases the size of the acute antiviral response and of the resulting memory T cell pool.J Immunol. 2002; 169: 4990-4997Crossref PubMed Scopus (28) Google Scholar Since IL-2 has also been found to overcome the proliferation block of anergic cells22Powell JD Ragheb JA Kitagawa-Sakakida S Schwartz RH Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy.Immunol Rev. 1998; 165: 287-300Crossref PubMed Scopus (160) Google Scholar as well as inhibition through the PD1:PD-L pathway,23Carter L Fouser LA Jussif J Fitz L Deng B Wood CR et al.PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.Eur J Immunol. 2002; 32: 634-643Crossref PubMed Scopus (559) Google Scholar a clear rationale for administration of IL-2 in cancer immunotherapy can be found in the literature. Indeed, systemic IL-2 therapy represents a contemporary treatment option and is associated with complete responses against a variety of cancers.24Coventry BJ Ashdown ML The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses.Cancer Manag Res. 2012; 4: 215-221Crossref PubMed Scopus (37) Google Scholar Notably, unremitting complete responses, i.e., cure from disease, are frequently reported,24Coventry BJ Ashdown ML The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses.Cancer Manag Res. 2012; 4: 215-221Crossref PubMed Scopus (37) Google Scholar but unfortunately, systemic delivery of IL-2 is hampered by dose-limiting toxicities.25Krieg C Létourneau S Pantaleo G Boyman O Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells.Proc Natl Acad Sci USA. 2010; 107: 11906-11911Crossref PubMed Scopus (225) Google Scholar As a consequence, low dose IL-2 has been suggested as an alternative treatment modality. However, this results in poor therapeutic scores with decreased protection, duration and quality of the responses.26Alexandrescu DT Ichim TE Riordan NH Marincola FM Di Nardo A Kabigting FD et al.Immunotherapy for melanoma: current status and perspectives.J Immunother. 2010; 33: 570-590Crossref PubMed Scopus (65) Google Scholar Furthermore, the short half-life of IL-2 (minutes),27Donohue JH Rosenberg SA The fate of interleukin-2 after in vivo administration.J Immunol. 1983; 130: 2203-2208PubMed Google Scholar necessitates frequent and recurrent administrations, unless complexed to an antibody.28Tomala J Chmelova H Mrkvan T Rihova B Kovar M In vivo expansion of activated naive CD8+ T cells and NK cells driven by complexes of IL-2 and anti-IL-2 monoclonal antibody as novel approach of cancer immunotherapy.J Immunol. 2009; 183: 4904-4912Crossref PubMed Scopus (72) Google Scholar An alternative delivery method, co-encoding the cytokine of interest with the vaccine antigen is not a completely new concept, and IL-2 is one among many cytokines that have been successfully explored as DNA vaccine adjuvants.29Senovilla L Vacchelli E Garcia P Eggermont A Fridman WH Galon J et al.Trial watch: DNA vaccines for cancer therapy.Oncoimmunology. 2013; 2: e23803Crossref PubMed Scopus (62) Google Scholar However, viral vectors come with an intrinsic adjuvanticity, and only a few reports have claimed improved efficacy of viral vectored vaccines through cytokine co-administration. Our results demonstrate that current adenoviral vaccine vectors can be improved and even tailored to meet specific demands, such as an augmented generation of antigen-specific effector CD8+ T cells. With the aim to study the impact of IL-2 expression from antigen-expressing adenoviral vectors on the immunogenicity of these vaccines, three new vaccine constructs were generated targeting either the GP or, for control, the nucleoprotein (NP) of LCMV (Ad5-IiGP-IL2, Ad5-GP-IL2, Ad5-NP-IL2). Initially we performed in vitro analyses to ascertain the functionality of our newly designed vaccine constructs in terms of IL-2 secretion and the biological activity of the secreted product. To this end, we infected immortalized APC-like JAWII cells30Jørgensen TN Haase C Michelsen BK Treatment of an immortalized APC cell line with both cytokines and LPS ensures effective T-cell activation in vitro.Scand J Immunol. 2002; 56: 492-503Crossref PubMed Scopus (24) Google Scholar at high multiplicity. As expected, cells infected with any of our IL-2 encoding constructs, acquired the capacity to secrete equal and biological functional amounts of IL-2 as demonstrated not only by standard ELISA titration (Supplementary Figure S1a), but also in a bioasssay of T cell proliferation (Supplementary Figure S1b) using in vivo generated virus-primed T-cell blasts as indicators of IL-2 activity.31Andersson EC Christensen JP Scheynius A Marker O Thomsen AR Lymphocytic choriomeningitis virus infection is associated with long-standing perturbation of LFA-1 expression on CD8+ T cells.Scand J Immunol. 1995; 42: 110-118Crossref PubMed Scopus (47) Google Scholar Regarding the importance of MOI on IL-2 secretion, cf. Supplementary Figure S1c. Next, we studied whether vector induced expression of IL-2 would augment the Ag-specific T-cell response elicited in WT mice. WT mice were vaccinated using either the conventional Ad5-IiGP construct or a similar construct co-expressing IL-2, and on days 7, 11, 14, 21, 48, and 300 p.i., numbers of Ag-specific CD8 T cells were determined. As can be seen in Figure 1a, the IL-2 encoding construct significantly augmented the primary CD8+ T-cell response compared to that elicited in Ad5-IiGP vaccinated mice, resulting in a significant increase in numbers of IFNγ producing Ag-specific T cells in the spleen 11–21 days post vaccination (p.v.) (for a set of representative dot plots, cf. Supplementary Figure S2). An important question connected with the finding of an increased effector T cell response is whether the frequency of circulating Tregs is similarly increased as this might potentially annul the beneficial effect of co-expressing IL-2 from APCs. However, when vaccinated mice were analyzed 11, 14, or 21 days after vaccination (Figure 2a), numbers of Tregs in the spleen were not significantly different whether the mice had been vaccinated using the IL-2 encoding construct or the conventional construct. Consistent with this absence of evidence for a systemic effect of IL-2 in mice vaccinated with the IL-2 expressing vector, we could not detect IL-2 in the circulation of these mice when serum was analyzed 3 days after local vaccination (<20 pg/ml serum), a time point at which protein expression is expected to be near its peak. To further study the action range of vector produced IL-2, we performed additional experiments in which groups of mice were co-infected in the same footpad with two different antigen-expressing constructs (NP or GP), only one of which co-expressed IL-2 at a time; as controls we used mice vaccinated with both antigens in the absence of vector encoded IL-2. As can be seen in Figure 2b,c, a statistically significant increase in numbers of antigen-specific effector CD8+ T cells was only observed when antigen and IL-2 were co-expressed from the same vector, indicating that the level of IL-2 produced from infected APCs in vivo was only sufficient to significantly impact T-cell activation in the immediate vicinity of these cells. The determinants for generation of an increased number of effector CD8+ T cells could be a number of factors including increased cell proliferation and/or decreased susceptibility to apoptosis. However, when we analyzed antigen-specific CD8+ T cells harvested from the spleen on day 9 p.v., at which time the difference between mice vaccinated with or without IL-2 encoded in the vector is still increasing (cf. Figure 1a), we did not observe a difference in the expression of neither the survival marker Bcl-2, nor the apoptotic marker Annexin-V (Figure 3a), though expression of both factors are known to be influenced by IL-2 stimulation.32Akbar AN Borthwick NJ Wickremasinghe RG Panayoitidis P Pilling D Bofill M et al.Interleukin-2 receptor common gamma-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression.Eur J Immunol. 1996; 26: 294-299Crossref PubMed Scopus (331) Google Scholar,33Kuroda K Yagi J Imanishi K Yan XJ Li XY Fujimaki W et al.Implantation of IL-2-containing osmotic pump prolongs the survival of superantigen-reactive T cells expanded in mice injected with bacterial superantigen.J Immunol. 1996; 157: 1422-1431PubMed Google Scholar To address if increased IL-2 production from APCs accelerated early T-cell proliferation, we made use of a transfer model where CSFE labeled TCR transgenic CD8+ or CD4+ T cells from either CD45.1 or CD45.2 donors are transferred into recipients expressing CD45.2 or CD45.1, respectively. One day later recipients were vaccinated using either construct, and 70 hours later CSFE dilution patterns in the draining lymph nodes were compared. As evident from Figure 3b, we could not detect altered proliferation patterns following IL-2 expression from the vector; neither in CD8+ nor CD4+ T cells. The latter has therapeutic relevance, since the timing of co-administered IL-2 is essential for proper CD4+ T-cell activation17Blattman JN Grayson JM Wherry EJ Kaech SM Smith KA Ahmed R Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo.Nat Med. 2003; 9: 540-547Crossref PubMed Scopus (309) Google Scholar and incorrect timing may impact the CD4 T-cell response negatively. Lastly, extended IL-2 secretion from the APCs may facilitate prolonged expression of the IL-2 receptor-alpha (CD25), which is recycled upon stimulation,34Malek TR The biology of interleukin-2.Annu Rev Immunol. 2008; 26: 453-479Crossref PubMed Scopus (772) Google Scholar hence causing a sustained activation phase. A likely net result from such a feed-back would be an increased number of circulating Ag-specific T cells at the peak of the adaptive immune response as we observed in our kinetics analysis (see Figure 1a), even if increased proliferation is not clearly discernible in our proliferation assay which, notably, is performed using high avidity TCR transgenic cells and at a higher concentration of antigen-specific cells than normally found at least during the early phase of antigen stimulation. In accordance with this hypothesis, we witnessed an up-regulation of CD25 expression on antigen-specific CD8+ T cells in the vaccine draining lymph nodes of IL-2 vaccinated mice on day 9 p.v.(Figure 3a). Of therapeutic importance, increased CD25 expression was not observed in the spleen, making this a local phenomenon restricted to the antigen presenting microenvironment, consistent with our findings regarding the short action range of the locally augmented IL-2 activity (Figure 2b,c). Notably, extended up-regulation of CD25 tends to favor terminal-effector differentiation,13Pipkin ME Sacks JA Cruz-Guilloty F Lichtenheld MG Bevan MJ Rao A Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.Immunity. 2010; 32: 79-90Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar,18Kalia V Sarkar S Subramaniam S Haining WN Smith KA Ahmed R Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo.Immunity. 2010; 32: 91-103Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar which could cause an augmented effector response at the expense of reduced T-cell memory. It is therefore important to note that expression of IL-2 from the vaccine construct did not significantly influence the phenotypes of the generated T cells nor did it have a negative impact on the number of antigen-specific CD8+ T cell found late after vaccination (Figure 1a,b, respectively). Similarly, regarding cytokine profiles these were identical with most cells producing IFNγ in combination with TNF-α as normally expected for primary effector CD8+ T cells induced by adenoviral immunization (data not shown). Normally, vaccination with adenoviral vectors requires CD4+ T-cell help for induction of a good CD8+ T-cell response.35Holst PJ Christensen JP Thomsen AR Vaccination against lymphocytic choriomeningitis virus infection in MHC class II-deficient mice.J Immunol. 2011; 186: 3997-4007Crossref PubMed Scopus (20) Google Scholar The above results seem to suggest that in Ad5 vaccinated WT mice the availability of IL-2 represents a limiting factor concerning the magnitude of the induced response. Since a key function of CD4+ Thelper cells during help-dependent primary CD8+ T-cell responses is to deliver IL-2,36Wiesel M Joller N Ehlert AK Crouse J Spörri R Bachmann MF et al.Th cells act via two synergistic pathways to promote antiviral CD8+ T cell responses.J Immunol. 2010; 185: 5188-5197Crossref PubMed Scopus (30) Google Scholar,37Wilson EB Livingstone AM Cutting edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses.J Immunol. 2008; 181: 7445-7448Crossref PubMed Scopus (70) Google Scholar,38Umeshappa CS Xie Y Xu S Nanjundappa RH Freywald A Deng Y et al.Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.PLoS ONE. 2013; 8: e64787Crossref PubMed Scopus (11) Google Scholar we next sought to address if employing an IL-2 encoding vaccine construct would diminish the necessity for CD4+ T-cell help during vaccination with adenoviral vectors. Importantly, in the construct used as reference so far, fusion of the expressed Ag to Ii, has previously been shown to minimize the requirement for CD4+ T-cell help in vivo.35Holst PJ Christensen JP Thomsen AR Vaccination against lymphocytic choriomeningitis virus infection in MHC class II-deficient mice.J Immunol. 2011; 186: 3997-4007Crossref PubMed Scopus (20) Google Scholar Accordingly, we vaccinated MHC-II deficient knockout mice employing a weaker vaccine construct encoding only GP, but not Ii, and again, either with or without co-expression of IL-2. As can be seen in Figure 4a, the inclusion of IL-2 in the vaccine construct reduced the requirement for CD4+ T-cell help, and the antigen-specific CD8+ T-cell response elicited with the IL-2 encoding construct in CD4 T-cell deficient mice roughly matched that induced in WT mice in the absence of IL-2. Thus, together our results with the IL-2 expressing construct suggest that availability of IL-2 is a key factor in regulating the magnitude of adenovector induced CD8+ T-cell responses and that a central role of CD4+ T cells is to produce sufficient amounts of endogenous IL-2. To further support a direct effect of IL-2 on the CD8+ T cells, we reconstituted lethally irradiated B6.SJL (CD45.1) mice with a mixture of bone marrow from CD25-/- (CD45.2) and CD25+/+ B6.SJL (CD45.1) mice. Ten weeks after reconstitution, the mice were vaccinated with Ad5-IiGP either with or without IL-2, and 11 days later antigen-specific CD8+ T cells of each genotype were enumerated (Figure 4b). While similar low numbers of effector cells were generated from CD25-/- donor cells, irrespectively of the vaccine construct used for immunization, expansion of WT cells tended to be greater following vaccination with the IL-2 expressing construct. Previously, we have shown that the Ad5-IiGP induced CD8+ T-cell mediated control of subcutanous (s.c.) GP33-expressing melanomas could parallel that associated with stimulation by live LCMV virus, which in many respects stands as a gold standard for CD8+ T-cell activation.4Sorensen MR Holst PJ Pircher H Christensen JP Thomsen AR Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control.Eur J Immunol. 2009; 39: 2725-2736Crossref PubMed Scopus (35) Google Scholar However, long-term survivors are still a rare phenomenon. Consequently, to see if we could improve the vaccine induced tumor control, we tested our IL-2 expressing construct under similar conditions. Thus we challenged WT mice with 106 B16.F10-GP melanoma cells s.c. followed by therapeutic vaccination with Ad5-IiGP or Ad5-IiGP-IL-2 5 days later. As can be seen in Figure 5a, the GP-specific, IL-2 encoding construct tended to prolong the survival. This effect is mediated by antigen-specific CD8+ T cells and not through a general, non-specific immune activation for two reasons. First, a similar construct encoding IL-2, but combined with an irrelevant antigen, LCMV NP, did not cause prolonged survival (Figure 5a). Similarly, if we challenged mice given the Ad-IiGP vaccine (±IL-2) with B16.F10 melanoma cells not expressing GP, there was no therapeutic effect of either vaccine (Figure 5b). While the difference between Ad5-IiGP and Ad5-IiGP-IL-2 vaccinated mice regarding survival following challenge with 106 tumor cells only reached the level of statistical significance if data from several experiments were pooled, we could obtain significant results in individual experiments when the tumor challenge dose was lowered 10-fold (Figure 5c,d); thus, by expressing IL-2 from the vaccine vector, we managed not only to prolong the survival time, but also to increase the proportion of long-term survivors to 50% as opposed to 10% without IL-2 expression from the vector. The above results encouraged us to test the potency of the IL-2 encoding construct in a model mimicking the immunodeficiency seen in the context of many human tumors. For this purpose, mice deficient in co-stimulation, CD80/86-/- mice, seemed appropriate: both APCs in the tumor environment and the tumor cells themselves usually show low expression of CD80 and CD86,1Gajewski TF Woo SR Zha Y Spaapen R Zheng Y Corrales L et al.Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment.Curr Opin Immunol. 2013; 25: 268-276Crossref PubMed Scopus (314) Google Scholar,6Rabinovich GA Gabrilovich D Sotomayor EM Immunosuppressive strategies that are mediated by tumor cells.Annu Rev Immunol. 2007; 25: 267-296Crossref PubMed Scopus (1288) Google Scholar and mice lacking these molecules are known to have a blunted immune response.39Borriello F Sethna MP Boyd SD Schweitzer AN Tivol EA Jacoby D et al.B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation.Immunity. 1997; 6: 303-313Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar,40Carreno BM Collins M The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses.Annu Rev Immunol. 2002; 20: 29-53Crossref PubMed Scopus (742) Google Scholar However, because CD80/86 engagement of CD28 is a direct mediator of IL-2 transcription,22Powell JD Ragheb JA Kitagawa-Sakakida S Schwartz RH Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy.Immunol Rev. 1998; 165: 287-300Crossref PubMed Scopus (160) Google Scholar we hypothesized that the IL-2 encoding construct could reverse the immunodeficiency in these mice. Indeed, when CD80/86-/- mice were vaccinated with the IL-2 encoding construct and antigen-specific CD8+ T cells in the spleen were enumerated 14 days later, these mice were found to harbor nearly as many primary effector CD8+ T cells as did matched WT mice, and at least as many as WT mice given the conventional vaccine (Figure 6b). However, at 11 days p.v.(Figure 6a) the response in Ad5-IiGP-IL-2 vaccinated CD80/86-/- mice was rather low compared to that in matched WT mice, pointing to a delayed, but still functional, CD8+ T-cell response in the former mice when vaccinated with the Ad-IiGP-IL-2 vector. To test the therapeutic p" @default.
• W2077632034 created "2016-06-24" @default.
• W2077632034 creator A5005415926 @default.
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• W2077632034 date "2014-12-01" @default.
• W2077632034 modified "2023-09-26" @default.
• W2077632034 title "Co-Expression of Tumor Antigen and Interleukin-2 From an Adenoviral Vector Augments the Efficiency of Therapeutic Tumor Vaccination" @default.
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