Abstract
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.
Highlights
Glioblastoma multiforme (GBM) is one of the most frequent and devastating brain tumors [1, 2]
This enhanced green fluorescent protein (EGFP)-expressing virus is derived from low-passage human cytomegalovirus (HCMV) strain TB40/E and contains an intact US-gene region encoding all immunoevasins (US2, US3, US6, and US11) that downregulate MHC class I presentation [44]
All GBM cell lines tested were susceptible to HCMV, infection the virus remained mostly cellassociated during the observation period of 12 days
Summary
Glioblastoma multiforme (GBM) is one of the most frequent and devastating brain tumors [1, 2]. Different forms of immunotherapy have been implemented or explored in a variety of human malignancies including GBM [4]. Adoptive transfer of genetically modified T cells may be an option in treatment of GBM [5,6,7,8]. Checkpoint inhibitors have failed to prolong the overall survival of patients with recurrent GBM [9,10,11]. Therapeutic cancer vaccines stimulating tumor-reactive CD8+ T cells represent another form of immunotherapy that has been tested in GBM patients [4, 13]
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