Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4<sup>+</sup> T‐cell‐independent CD8<sup>+</sup> T‐cell‐mediated tumor control

Sørensen, Maria Rathmann; Holst, Peter Johannes; Pircher, Hanspeter; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

doi:10.1002/eji.200939543

Cited by 42 publications

(50 citation statements)

References 37 publications

(47 reference statements)

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“…Most important, in both experimental setups, tumor control was limited compared with that observed in mice vaccinated with Ad-Ii-GP, thus targeting a non-self-Ag. It is generally acknowledged that CD8 T cells are key players in immune-mediated tumor degradation, and our previous studies have also demonstrated that the Ad-Ii-GP-induced tumor control is dependent on an improved CD8 T cell response as well as IFN-g (16). Thus, we concluded that the reason for the difference in tumor control had to reflect differences in numbers and/or quality of vaccine-induced CD8 T cells depending on their specificity for selfversus non-self-Ags.…”

Section: Discussionmentioning

confidence: 83%

“…Generally, viruses seem to induce exactly the type of immune response that would be expected to be optimal for efficient tumor control. Consequently, having established an improved platform for anti-infective vaccination using a replication deficient adenovirus, Ad-Ii-GP, we previously tested this vector against tumor cells expressing a viral epitope, namely the LCMV GP (33), and found significant protection (16,59). Notably, this was the case even in hosts expressing the targeted viral epitope as a self-Ag in the pancreas.…”

Section: Discussionmentioning

confidence: 99%

“…1A). These results stand in clear contrast to our previous experience with prophylactic vaccination with Ad-Ii-GP, which we had found to completely prevent tumor-associated death in mice challenged with B16.F10gp s.c. (16).…”

Section: Adenoviral Vaccines Targeting Self-melanoma Tas Do Not Inducmentioning

confidence: 99%

“…Our group has already used this vaccination strategy in a murine melanoma model, and it has given very promising results. Thus, we have previously demonstrated complete protection against B16.F10gp melanoma cells after prophylactic vaccination with an adenoviral vector encoding the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) (16). Because B16.F10gp cells have been modified to express GP [33][34][35][36][37][38][39][40][41] , the immunodominant MHC class I epitope of the LCMV GP, this experimental setup should mimic a situation with the presence of a foreign virus-encoded tumor Ag (TA), for example, as is the case in human papillomavirus-positive cervical cancers.…”

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confidence: 99%

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Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Pedersen

Sørensen

Buus

et al. 2013

The Journal of Immunology

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It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA–specific CD8 T cell response and compare it to that induced against non–self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA–specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non–self-Ag–specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA–specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Adenoviral Vaccines Targeting Self-melanoma Tas Do Not Inducmentioning

confidence: 99%

mentioning

confidence: 99%

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Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Pedersen

Sørensen

Buus

et al. 2013

The Journal of Immunology

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“…Absence of a dominant epitope in an Ii-linked construct may dramatically increase subdominant responses Linking the vaccine Ag expressed from an adenoviral vector to the MHC class II-associated Ii has proved successful in eliciting increased numbers of Ag-specific CD8 + T cells in several studies (29,30,(35)(36)(37). However, the effect of Ii linkage varies with the selected Ag, and we have previously observed that the NP of LCMV does not seem to benefit from Ii linkage in terms of numbers of NP396 (dominant epitope)-specific CD8 + T cells and protection from LCMV infection (24) (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

Steffensen

Pedersen

Jahn

et al. 2016

The Journal of Immunology

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As a result of the difficulties in making efficient vaccines against genetically unstable viruses such as HIV, it has been suggested that future vaccines should preferentially target subdominant epitopes, the idea being that this should allow a greater breadth of the induced T cell response and, hence, a greater efficiency in controlling escape variants. However, to our knowledge the evidence supporting this concept is limited at best. To improve upon this, we used the murine lymphocytic choriomeningitis virus model and adenoviral vectors to compare a vaccine expressing unmodified Ag to a vaccine expressing the same Ag without its immunodominant epitope. We found that removal of the dominant epitope allowed the induction of CD8+ T cell responses targeting at least two otherwise subdominant epitopes. Importantly, the overall magnitude of the induced T cell responses was similar, allowing us to directly compare the efficiency of these vaccines. Doing this, we observed that mice vaccinated with the vaccine expressing unmodified Ag more efficiently controlled an acute viral challenge. In the course of a more chronic viral infection, mice vaccinated using the vaccine targeting subdominant epitopes caught up with the conventionally vaccinated mice, and analysis of the breadth of the CD8+ T cell response revealed that this was notably greater in the former mice. However, under the conditions of our studies, we never saw any functional advantage of this. This may represent a limitation of our model, but clearly our findings underscore the importance of carefully weighing the pros and cons of changes in epitope targeting before any implementation.

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Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T‐cell activation

et al. 2013

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IntroductionSuccessful vaccination depends on activation of CD8 + and CD4 + T-cell responses by presentation of antigenic peptides in the context of major histocompatibility complex class I (MHCI) and II Correspondence: Dr. Tone F. Gregers e-mail: t.f.gregers@ibv.uio.no (MHCII) molecules, respectively. The processing and subsequent presentation of antigenic peptides by MHCI or MHCII molecules on the surface of antigen presenting cells (APCs) requires a coordinated action of different accessory molecules and dedicated chaperones. Targeting of Ags to these pathways that * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 774-784 Immunomodulation 775 improve presentation to T cells, would therefore be expected to potentiate vaccine strategies. MHCII interacts with the dedicated chaperone invariant chain (Ii) in the ER. Ii contains sorting signals within its cytoplasmic tail, which mediate trafficking of Ii-MHCII to proteolytic endosomal compartments where Ag loading takes place [1]. In the endosomal pathway Ii is sequentially degraded, leaving a residual CLIP in the peptide-binding groove of MHCII, which is exchanged by specific antigenic peptides by the action of HLA-DM.Indeed, Ags targeted to the endosomal pathway for loading onto MHCII have successfully been shown to activate CD4 + T-cell responses. Ag targeting has been achieved using signals associated with lysosomal proteins, such as lysosomal-associated membrane protein 1 [2] or other lysosomal hydrolases [3], by direct coupling of the Ag to full-length Ii, or to Ii containing the endosomal localization signal only [4,5]. Finally, genetic exchange of the CLIP sequence with antigenic epitopes was demonstrated to be highly efficient for loading of MHCII and CD4 + T-cell activation [6]. In fact, this strategy has proven to be superior compared to peptide loading for priming of CD4 + T cells and tumor protection in vivo [7, 8].Loading of MHCI molecules for vaccine purposes has commonly been achieved by exogenous pulsing of APCs with synthetic peptides in vitro. This approach is limited by rapid degradation of peptides, the risk of inducing T-cell tolerance [9], and the possibility for the formation of cryptic epitopes leading to imprecise tumor targeting [10]. Another alternative is Ag delivery by mRNA [11] or DNA [12], relying on protein production and proteasomal degradation to generate high peptide concentrations in the cytosol of the APC. Peptides are subsequently translocated into the ER by transporters associated with Ag processing (TAP), and loaded onto MHCI [11]. However, vaccination strategies that are independent of proteasomal degradation might represent an advantage in several contexts. Some tumor Ags are processed more efficiently by the immunoproteasomes of dendritic cells (DCs) than by the standard proteasomes present in the majority of other cells, whereas for others the situation is vice versa [13,14]. Moreover, the combination of immunotherapy with certain...

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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

Cited by 42 publications

References 37 publications

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T‐cell activation

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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

Cited by 42 publications

References 37 publications

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Comparison of Vaccine-Induced Effector CD8 T Cell Responses Directed against Self- and Non–Self-Tumor Antigens: Implications for Cancer Immunotherapy

Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

Invariant chain as a vehicle to load antigenic peptides on human MHC class I for cytotoxic T‐cell activation

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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