The essentially monomorphic human antigen presentation molecule HLA-E is an interesting candidate target to enable vaccination irrespective of genetic diversity. Predictive HLA-E peptide-binding... Show moreThe essentially monomorphic human antigen presentation molecule HLA-E is an interesting candidate target to enable vaccination irrespective of genetic diversity. Predictive HLA-E peptide-binding motifs have been refined to facilitate HLA-E peptide discovery. HLA-E can accommodate structurally divergent peptides of both self and microbial origin. Intracellular processing and presentation pathways for peptides by HLA-E for T cell receptor (TCR) recognition remain to be elucidated. Recent studies show that, unlike canonical peptides, inhibition of the transporter associated with antigen presentation (TAP) is essential to allow HLA-E antigen presentation in cytomegalovirus (CMV) infection and possibly also of other noncanonical peptides. We propose three alternative and TAP-independent MHC-E antigen-presentation pathways, including for Mycobacterium tuberculosis infections. These insights may help in designing potential HLA-E targeting vaccines against tumors and pathogens. Show less
Weitering, T.J.; Takada, S.; Weemaes, C.M.R.; Schouwenburg, P.A. van; Burg, M. van der 2021
ATM is often dubbed the master regulator of the DNA double stranded break (DSB) response. Since proper induction and repair of DNA DSBs forms the core of immunological diversity, it is surprising... Show moreATM is often dubbed the master regulator of the DNA double stranded break (DSB) response. Since proper induction and repair of DNA DSBs forms the core of immunological diversity, it is surprising that patients with ataxia telangiectasia generally have a mild immunodeficiency in contrast to other DSB repair syndromes. In this review, we address this discrepancy by delving into the functions of ATM in DSB repair and cell cycle control and translate these to adaptive immunity. We conclude that ATM, despite its myriad functions, is not an absolute requirement for acquiring sufficient levels of immunological diversity to prevent severe viral and opportunistic infections. There is, however, a more clinically pronounced antibody deficiency in ataxia telangiectasia due to disturbed class switch recombination. Show less
Inhibitory and stimulatory immune checkpoint molecules play important roles in regulating immune responses. An increasing number of these immune regulators are currently being evaluated as targets... Show moreInhibitory and stimulatory immune checkpoint molecules play important roles in regulating immune responses. An increasing number of these immune regulators are currently being evaluated as targets in putative anti-cancer therapies. Recently, sophisticated genetic screens have been performed to increase our understanding of immune checkpoint pathways and their immunomodulatory regulators. Here, we summarize novel insights obtained by these screens and discuss new directions to advance possible strategies to treat malignancies. Show less
Zanden, S.Y. van der; Luimstra, J.J.; Neefjes, J.; Borst, J.; Ovaa, H. 2020
Cancer immunotherapy has proven remarkably successful through instigation of systemic antitumor T cell responses. Despite this achievement, further advancements are needed to expand the scope of... Show moreCancer immunotherapy has proven remarkably successful through instigation of systemic antitumor T cell responses. Despite this achievement, further advancements are needed to expand the scope of susceptible cancer types and overcome variation in treatment outcomes between patients. Small-molecule drugs targeting defined pathways and/or cells capable of immune modulation are expected to substantially improve efficacy of cancer immunotherapy. Small-molecule drugs possess unique properties compatible with systemic administration and amenable to both extracellular and intracellular targets. These compounds can modify molecular pathways to overcome immune tolerance and suppression towards effective antitumor responses. Here, we provide an overview of how such effects might be achieved by combining immunotherapy with conventional and/or new small-molecule chemotherapeutics. Show less
Groeneveldt, C.; Hall, T. van; Burg, S.H. van der; Dijke, P. ten; Montfoort, N. van 2020
In cancer immunotherapy, a patient's own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly... Show moreIn cancer immunotherapy, a patient's own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-beta (TGF-beta)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-beta signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade. Show less
Persistent viral infections reflect a failure of the host's immune system to control infection, and in many cases, they are associated with the development of malignancies. So far, vaccines... Show morePersistent viral infections reflect a failure of the host's immune system to control infection, and in many cases, they are associated with the development of malignancies. So far, vaccines designed to boost viral immunity during chronic infection have not been successful. Infections with high-risk human papilloma viruses (e.g. HPV16) are acquired by a large segment of the population and persist in 5-10% of infected individuals, which causes the development of high-grade pre-malignant lesions. Recently we succeeded in causing regression of HPV16-induced disease in similar to 50% of chronically infected patients by a novel therapeutic vaccine. Here, we summarize the parallels in immunity against HPV and other chronic viruses and discuss the general implications of our findings for the immunotherapy of chronic infections. Show less
Burg, S.H. van der; Arens, R.; Melief, C.J.M. 2011
Persistent viral infections reflect a failure of the host's immune system to control infection, and in many cases, they are associated with the development of malignancies. So far, vaccines... Show morePersistent viral infections reflect a failure of the host's immune system to control infection, and in many cases, they are associated with the development of malignancies. So far, vaccines designed to boost viral immunity during chronic infection have not been successful. Infections with high-risk human papilloma viruses (e.g. HPV16) are acquired by a large segment of the population and persist in 5-10% of infected individuals, which causes the development of high-grade pre-malignant lesions. Recently we succeeded in causing regression of HPV16-induced disease in ∼50% of chronically infected patients by a novel therapeutic vaccine. Here, we summarize the parallels in immunity against HPV and other chronic viruses and discuss the general implications of our findings for the immunotherapy of chronic infections. Show less
