Development of a Human Cytomegalovirus (HCMV)-Based Therapeutic Cancer Vaccine Uncovers a Previously Unsuspected Viral Block of MHC Class I Antigen Presentation

Human cytomegalovirus (HCMV) induces a uniquely high frequency of virus-specific effector/memory CD8+ T-cells, a phenomenon termed “memory inflation”. Thus, HCMV-based vaccines are particularly interesting in order to stimulate a sustained and strong cellular immune response against cancer. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high lethality and inevitable relapse. The current standard treatment does not significantly improve the desperate situation underlining the urgent need to develop novel approaches. Although HCMV is highly fastidious with regard to species and cell type, GBM cell lines are susceptible to HCMV. In order to generate HCMV-based therapeutic vaccine candidates, we deleted all HCMV-encoded proteins (immunoevasins) that interfere with MHC class I presentation. The aim being to use the viral vector as an adjuvant for presentation of endogenous tumor antigens, the presentation of high levels of vector-encoded neoantigens and finally the repurposing of bystander HCMV-specific CD8+ T cells to fight the tumor. As neoantigen, we exemplarily used the E6 and E7 proteins of human papillomavirus type 16 (HPV-16) as a non-transforming fusion protein (E6/E7) that covers all relevant antigenic peptides. Surprisingly, GBM cells infected with E6/E7-expressing HCMV-vectors failed to stimulate E6-specific T cells despite high level expression of E6/E7 protein. Further experiments revealed that MHC class I presentation of E6/E7 is impaired by the HCMV-vector although it lacks all known immunoevasins. We also generated HCMV-based vectors that express E6-derived peptide fused to HCMV proteins. GBM cells infected with these vectors efficiently stimulated E6-specific T cells. Thus, fusion of antigenic sequences to HCMV proteins is required for efficient presentation via MHC class I molecules during infection. Taken together, these results provide the preclinical basis for development of HCMV-based vaccines and also reveal a novel HCMV-encoded block of MHC class I presentation

The E6E7 oncoproteins of cutaneous human papillomavirus type 38 interfere with the interferon pathway

Non-melanoma skin cancer is the most frequent malignancy in Caucasian populations. Evidence suggests the involvement of cutaneous Human Papillomavirus (HPV) of the genus beta () in this disease. The ability of E6 and E7 of mucosal HPV to promote cellular transformation and inhibit immune response-related pathways plays a key role in cervical carcinogenesis. HPV-38 E6 and E7 display transforming activities in in vitro and in vivo models, but their impact on immune surveillance is unknown. Here we show that HPV-38 E6 and E7 affect the IFN-induced up-regulation of MHC class I. Expression of the two viral proteins in HaCaT keratinocytes led to a decrease of MHC I levels. This down-regulation is associated with a reduction of expression of MHC I heavy chain, of the peptide chaperone TAP and of the STAT-1 downstream effector IRF-1. The down-regulation of these proteins is ultimately due to the inhibition of STAT-1 expression. Analysis of cells expressing either HPV-38 E6 or E7 suggests that these effects are primarily the result of E6 expression, although a contribution by E7 cannot be excluded. We conclude that HPV-38 encodes oncoproteins that potentially contribute to the evasion of host immune surveillance

Gauge Coupling Unification in E6 F-Theory GUTs with Matter and Bulk Exotics from Flux Breaking

We consider gauge coupling unification in E6 F-Theory Grand Unified Theories (GUTs) where E6 is broken to the Standard Model (SM) gauge group using fluxes. In such models there are two types of exotics that can affect gauge coupling unification, namely matter exotics from the matter curves in the 27 dimensional representation of E6 and the bulk exotics from the adjoint 78 dimensional representation of E6. We explore the conditions required for either the complete or partial removal of bulk exotics from the low energy spectrum. In the latter case we shall show that (miraculously) gauge coupling unification may be possible even if there are bulk exotics at the TeV scale. Indeed in some cases it is necessary for bulk exotics to survive to the TeV scale in order to cancel the effects coming from other TeV scale matter exotics which would by themselves spoil gauge coupling unification. The combination of matter and bulk exotics in these cases can lead to precise gauge coupling unification which would not be possible with either type of exotics considered by themselves. The combination of matter and bulk exotics at the TeV scale represents a unique and striking signature of E6 F-theory GUTs that can be tested at the LHC.Comment: 21 pages, 5 figure

Mapping the geometry of the E6 group

In this paper we present a construction for the compact form of the exceptional Lie group E6 by exponentiating the corresponding Lie algebra e6, which we realize as the the sum of f4, the derivations of the exceptional Jordan algebra J3 of dimension 3 with octonionic entries, and the right multiplication by the elements of J3 with vanishing trace. Our parametrization is a generalization of the Euler angles for SU(2) and it is based on the fibration of E6 via a F4 subgroup as the fiber. It makes use of a similar construction we have performed in a previous article for F4. An interesting first application of these results lies in the fact that we are able to determine an explicit expression for the Haar invariant measure on the E6 group manifold.Comment: 30 page

Octonionic Cayley Spinors and E6

Attempts to extend our previous work using the octonions to describe fundamental particles lead naturally to the consideration of a particular real, noncompact form of the exceptional Lie group E6, and of its subgroups. We are therefore led to a description of E6 in terms of 3x3 octonionic matrices, generalizing previous results in the 2x2 case. Our treatment naturally includes a description of several important subgroups of E6, notably G2, F4, and (the double cover of) SO(9,1), An interpretation of the actions of these groups on the squares of 3-component "Cayley spinors" is suggested.Comment: 14 pages, 1 figure, contributed talk at 2nd Mile High Conference (Denver 2009

A Light Z' Heterotic-String Derived Model

The existence of an extra Z' inspired from heterotic-string theory at accessible energy scales attracted considerable interest in the particle physics literature. Surprisingly, however, the construction of heterotic--string derived models that allow for an extra Z' to remain unbroken down to low scales has proven to be very difficult. The main reason being that the U(1) symmetries that are typically discussed in the literature are either anomalous or have to be broken at a high scale to generate light neutrino masses. In this paper we use for that purpose the self duality property under the spinor vector duality, which was discovered in free fermionic heterotic-string models. The chiral massless states in the self--dual models fill complete 27 representations of E6. The anomaly free gauge symmetry in the effective low energy field theory of our string model is $SU(4)_C\times SU(2)_L\times SU(2)_R\times U(1)_\zeta$, where $U(1)_\zeta$ is the family universal $U(1)$ symmetry that descends from E6, and is typically anomalous in other free fermionic heterotic-string models. Our model therefore allows for the existence of a low scale Z', which is a combination of $B-L$, $T_{3_L}$ and $T_{3_R}$. The string model is free of exotic fractionally charged states in the massless spectrum. It contains exotic SO(10) singlet states that carry fractional, non--E6 charge, with respect to $U(1)_\zeta$. These non-E6 states arise in the string model due to the breaking of the E6 symmetry by discrete Wilson lines. They represent a distinct signature of the string vacua and cannot arise in E6 Grand Unified Theories. They may provide viable dark matter candidates.Comment: 18 pages. Standard LaTeX. 3 table