Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high... Show moreImmune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional sin-gle-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict re-sponses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for ther-apy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy. Show less
Pardieck, I.N.; Duikeren, S. van; Veerkamp, D.M.B.; Brasem, D.J.; Redeker, A.; Bergen, J. van; ... ; Arens, R. 2022
Human cytomegalovirus (HCMV) is an ubiquitous herpesvirus that can cause serious morbidity and mortality in immunocompromised or immune-immature individuals. A vaccine that induces immunity to CMV... Show moreHuman cytomegalovirus (HCMV) is an ubiquitous herpesvirus that can cause serious morbidity and mortality in immunocompromised or immune-immature individuals. A vaccine that induces immunity to CMV in these target populations is therefore highly needed. Previous attempts to generate efficacious CMV vaccines primarily focused on the induction of humoral immunity by eliciting neutralizing antibodies. Current insights encourage that a protective immune response to HCMV might benefit from the induction of virus-specific T cells. Whether addition of antiviral T cell responses enhances the protection by antibody-eliciting vaccines is however unclear. Here, we assessed this query in mouse CMV (MCMV) infection models by developing synthetic vaccines with humoral immunity potential, and deliberately adding antiviral CD8(+) T cells. To induce antibodies against MCMV, we developed a DNA vaccine encoding either full-length, membrane bound glycoprotein B (gB) or a secreted variant lacking the transmembrane and intracellular domain (secreted (s)gB). Intradermal immunization with an increasing dose schedule of sgB and booster immunization provided robust viral-specific IgG responses and viral control. Combined vaccination of the sgB DNA vaccine with synthetic long peptides (SLP)-vaccines encoding MHC class I-restricted CMV epitopes, which elicit exclusively CD8(+) T cell responses, significantly enhanced antiviral immunity. Thus, the combination of antibody and CD8(+) T cell-eliciting vaccines provides a collaborative improvement of humoral and cellular immunity enabling enhanced protection against CMV. Show less
Comprehensive analysis of CD8(+) T cell populations specific to cytomegalovirus reveals that the evolution of the T cell antigen receptor repertoire during chronic infections is characterized by... Show moreComprehensive analysis of CD8(+) T cell populations specific to cytomegalovirus reveals that the evolution of the T cell antigen receptor repertoire during chronic infections is characterized by the expansion of low-affinity clones. Show less
Othman, A.S.; Franke-Fayard, B.M.; Imai, T.; Gracht, E.T.I. van der; Redeker, A.; Salman, A.M.; ... ; Khan, S.M. 2018
The phenotype and functionality that CD8+ T cells acquire upon encountering their cognate antigen depend on many factors that are controlled by the nature of the pathogen The acquired... Show moreThe phenotype and functionality that CD8+ T cells acquire upon encountering their cognate antigen depend on many factors that are controlled by the nature of the pathogen The acquired phenotypical and functional characteristics determine the potential of the CD8+ T cells to form bona fide memory populations that are able to expand upon secondary challenge. We investigated factors that control CD8+ T cell differentiation. We have shown that the height of the viral dose greatly impacts the immunological outcome by affecting the magnitude of the response and the phenotype and function of the (memory) CD8+ T cells that are induced. The acquired phenotype and functions determine the capacity to expand upon re-encounter with the same pathogen and we have shown that the IL-2 producing capacity of CD8+ T cells functions as a crucial determinant of CD8+ T cell expansion potential. Although we addressed only a small fraction of all variables involved in the induction and maintenance of antigen-specific T cell populations our observations and insights gathered by others already provide a basis for rational immunotherapeutic treatment design, however, for fine-tuning of therapy-induced immune responses aspects about e.g. the timing and cooperating signals still need to be understood in more detail. Show less
Immune complexes are potent mediators of cellular immunity and have been extensively studied for their disease mediating properties in humans and for their role in anti-cancer immunity. However, a... Show moreImmune complexes are potent mediators of cellular immunity and have been extensively studied for their disease mediating properties in humans and for their role in anti-cancer immunity. However, a viable approach to use antibody-complexed antigen as vehicle for specific immunotherapy has not yet reached clinical use. Since virtually all people have endogenous antibodies against tetanus toxoid (TTd), such commonly occurring antibodies are promising candidates to utilize for immune modulation. As an initial proof-of-concept we investigated if anti-tetanus IgG could induce potent cross-presentation of a conjugate with SIINFEKL, a MHC class I presented epitope of ovalbumin (OVA), to TTd. This protein conjugate enhanced OVA-specific CD8+ T cell responses when administrated to seropositive mice. Since TTd is poorly defined, we next investigated whether a synthetic peptide-peptide conjugate, with a chemically defined linear B cell epitope of tetanus toxin (TTx) origin, could improve cellular immune responses. Herein we identify one linear B cell epitope, here after named MTTE thru a screening of overlapping peptides from the alpha and beta region of TTx, and by assessment of the binding of pooled IgG, or individual human IgG from high-titer TTd vaccinated donors, to these peptides. Subsequently, we developed a chemical protocol to synthesize defined conjugates containing multiple copies of MTTE covalently attached to one or more T cell epitopes of choice. To demonstrate the potential of the above approach we showed that immune complexes of anti-MTTE antibodies with MTTE-containing conjugates are able to induce DC and T cell activation using model antigens. Show less
Jackson, S.E.; Redeker, A.; Arens, R.; Baarle, D. van; Berg, S.P.H. van den; Benedict, C.A.; ... ; Wills, M.R. 2017