Improved methods for predicting peptide binding affinity to <scp>MHC</scp> class <scp>II</scp> molecules

Jensen, Kamilla Kjærgaard; Andreatta, Massimo; Marcatili, Paolo; Buus, Søren; Greenbaum, Jason A.; Zhen, Yan; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

doi:10.1111/imm.12889

Cited by 649 publications

(682 citation statements)

References 36 publications

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“…The NetMHCIIpan 3.2 Server, which represents the currently most accurate tool for predicting major histocompatibility complex (MHC) class II peptide-binding affinities, was used to predict epitopes 18. The NR1 protein sequence obtained from the National Center for Biotechnology Information (accession number NP_015566.1) was submitted to the server.…”

Section: Methodsmentioning

confidence: 99%

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Shu

Qiu

Zheng

et al. 2019

J Neurol Neurosurg Psychiatry

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Background and objectiveAetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus.MethodsHLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study.ResultsOur results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10−5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02.ConclusionsThis study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

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Section: Methodsmentioning

confidence: 99%

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Shu

Qiu

Zheng

et al. 2019

J Neurol Neurosurg Psychiatry

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“…The binding affinities of each peptide to MHC Class II molecules can be examined (48)(49)(50). Recently the adoptive CD4 + T cell therapy using an MHC class II-restricted TCR that recognized MAGE-A3 (cancer germline antigen) was investigated in a clinical trial (51).…”

Section: Discussionmentioning

confidence: 99%

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor–Engineered T Cells for Ovarian Cancer

Matsuda

Leisegang

Park

et al. 2018

Clinical Cancer Research

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To prepare Translational relevanceAdoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells is considered as a promising novel immunotherapy strategy. It takes four steps to prepare; (1) prediction of neoantigen epitopes, (2) neoantigen peptides synthesis, (3) identification of neoantigen-specific TCR and (4) production of virus vector to express TCR. Among them, the most challenging part is identification of neoantigen-specific TCRs. Our protocol required only two weeks from stimulation of T cells with peptides to the identification of neoantigen-specific TCRs. We conducted a pilot study to validate our time-efficient protocol in solid cancers with relatively lower mutational loads such as ovarian cancer. We successfully induced neoantigen-specific T cells against three neoantigens and established corresponding TCR-engineered T cells. One case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. These results give an important insight into the clinical application of adoptive T cell therapy with neoantigen-specific TCR-engineered T cells.Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 2, 2018; DOI: 10.1158/1078-0432.CCR-18-0142 4 ABSTRACTPurpose: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host antitumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only two weeks from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol. Experimental Design: We used tumors from 7 ovarian cancer patients to validate our protocol.Results: We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient), and then successfully induced 3 neoantigen-specific T cells from one healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells which recognized the corresponding neoantigens and showed cytotoxic activity in an antigendose-dependent manner. However, one case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. Conclusion/discussions: This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validati...

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“…With the development of next‐generation sequencing and bioinformatics strategies for in silico prediction, it is now possible to rapidly identify and filter neoantigens. WES of tumour samples allows identification of somatic mutations, which are modelled using a protein prediction algorithm and fed into an MHC‐binding predictor to model the MHC‐binding capacity. Structural variants (in particular, gene fusions that may also generate neoantigens) are more difficult to identify from WES unless RNA sequencing data are available.…”

Section: Colorectal Cancer Tumour Microenvironmentmentioning

confidence: 99%

Mechanisms of immunogenicity in colorectal cancer

Sillo

Beggs

Morton

et al. 2019

British Journal of Surgery

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Background The immune response in cancer is increasingly understood to be important in determining clinical outcomes, including responses to cancer therapies. New insights into the mechanisms underpinning the immune microenvironment in colorectal cancer are helping to develop the role of immunotherapy and suggest targeted approaches to the management of colorectal cancer at all disease stages. Method A literature search was performed in PubMed, MEDLINE and Cochrane Library databases to identify relevant articles. This narrative review discusses the current understanding of the contributors to immunogenicity in colorectal cancer and potential applications for targeted therapies. Results Responsiveness to immunotherapy in colorectal cancer is non‐uniform. Several factors, both germline and tumour‐related, are potential determinants of immunogenicity in colorectal cancer. Current approaches target tumours with high immunogenicity driven by mutations in DNA mismatch repair genes. Recent work suggests a role for therapies that boost the immune response in tumours with low immunogenicity. Conclusion With the development of promising therapies to boost the innate immune response, there is significant potential for the expansion of the role of immunotherapy as an adjuvant to surgical treatment in colorectal cancer.

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Improved methods for predicting peptide binding affinity to MHC class II molecules

Cited by 649 publications

References 36 publications

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

HLA class II alleleDRB1*16:02is associated with anti-NMDAR encephalitis

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor–Engineered T Cells for Ovarian Cancer

Mechanisms of immunogenicity in colorectal cancer

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