Estimating HLA haplotype frequencies from homozygous individuals – A Technical Report

Seitz, Susanne; Lange, Vinzenz; Norman, Paul J.; Sauter, Jürgen; Schmidt, Alexander H.

doi:10.1111/iji.12553

Cited by 9 publications

(17 citation statements)

References 25 publications

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“…Furthermore, we demonstrated that the H3K27M peptide vaccine induces an immune response across diverse HLA alleleotypes: the deconvoluted HLA restrictions of cognate CD4 + TCRs demonstrate restrictions to members of multiple class II HLA loci. DRB1*13:02 and DQB1*06:03 frequently co-occur on the same haplotype, whereas DRB1*07:01 and DQB1*06 are not a common haplotype pair 25 . Considering these allelic frequencies and the TCRs described in this work with their restrictions, 40-45% of the German population (where the INTERCEPT-H3 trial -NCT04808245 -is currently ongoing) could be covered with cell therapy using a pair of identified TCRs.…”

Section: Discussionmentioning

confidence: 94%

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Boschert

Kromer

Lerner

et al. 2023

Preprint

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H3K27M, a driver mutation with T- and B-cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient who was treated with an H3K27M peptide vaccine and subsequently entered complete remission. The vaccine robustly expanded class II HLA-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their CDR3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ, and -DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

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Section: Discussionmentioning

confidence: 94%

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Boschert

Kromer

Lerner

et al. 2023

Preprint

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“…For alleles DRB1*04:07g and DRB1*16:02g, both of which are present in virtually all Native populations from North, Central and South America, but also in Europe (DRB1*04:07g) and Asia (DRB1*16:02g), the examination of the DQB1 associations is distinctive. DRB1*04:07~DQB1*03:02 is a conserved Native American haplotype block while DRB1*04:07~DQB1*03:01 is found in Europeans ( 65 , 67 ). Similarly, DRB1*16:02~DQB1*03:01 is found in Native Americans while DRB1*16:02~DQB1*05:02 is typically seen in Asians and Africans ( 61 , 64 ).…”

Section: Discussionmentioning

confidence: 99%

HLA allele and haplotype frequencies of registered stem cell donors in Chile

Solloch,

Giani,

Pattillo Garnham

et al. 2023

Front. Immunol.

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Patients in need of hematopoietic stem cell transplantation often rely on unrelated stem cell donors matched in certain human leukocyte antigen (HLA) genes. Donor search is complicated by the extensive allelic variability of the HLA system. Therefore, large registries of potential donors are maintained in many countries worldwide. Population-specific HLA characteristics determine the registry benefits for patients and also the need for further regional donor recruitment. In this work, we analyzed HLA allele and haplotype frequencies of donors of DKMS Chile, the first Chilean donor registry, with self-assessed “non-Indigenous” (n=92,788) and “Mapuche” (n=1,993) ancestry. We identified HLA alleles that were distinctly more abundant in the Chilean subpopulations than in worldwide reference populations, four of them particularly characteristic for the Mapuche subpopulation, namely B*39:09g, B*35:09, DRB1*04:07g, and DRB1*16:02g. Both population subsamples carried haplotypes of both Native American and European origin at high frequencies, reflecting Chile’s complex history of admixture and immigration. Matching probability analysis revealed limited benefits for Chilean patients (both non-Indigenous and Mapuche) from donor registries of non-Chilean donors, thus indicating a need for ongoing significant donor recruitment efforts in Chile.

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“…Furthermore, we demonstrated that the H3K27M peptide vaccine induces an immune response across diverse HLA alleleotypes: The deconvoluted HLA restrictions of cognate CD4 + TCRs demonstrate restrictions to members of multiple class II HLA loci. DRB1*13:02 and DQB1*06:03 frequently co-occur on the same haplotype, whereas DRB1*07:01 and DQB1*06 are not a common haplotype pair ( 29 ). Considering these allelic frequencies and the TCRs described in this work with their restrictions, 40 to 45% of the German population (where the INTERCEPT-H3 trial, NCT04808245, is currently ongoing) could be covered with cell therapy using a pair of identified TCRs.…”

Section: Discussionmentioning

confidence: 99%

H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient

Boschert,

Kromer,

Lerner

et al. 2024

Sci. Adv.

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H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)–restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II–restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

show abstract

Estimating HLA haplotype frequencies from homozygous individuals – A Technical Report

Cited by 9 publications

References 25 publications

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

HLA allele and haplotype frequencies of registered stem cell donors in Chile

H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient

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