Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

Pagliuca, Simona; Gurnari, Carmelo; Hong, Sanghee; Zhao, Ran; Kongkiatkamon, Sunisa; Terkawi, Laila; Zawit, Misam; Guan, Yihong; Awada, Hassan; Kishtagari, Ashwin; Kerr, Cassandra M; LaFramboise, Thomas; Patel, Bhumika J.; Jha, Babal K.; Carraway, Hetty E.; Visconte, Valeria; Majhail, Navneet S.; Hamilton, Betty K.; Maciejewski, Jaroslaw P.

doi:10.1172/jci.insight.149080

Cited by 16 publications

(18 citation statements)

References 41 publications

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“…The top 10 clones in blood and gut of allogeneic recipients were not detectable in pre-transplant donor T cells ( Figures 4E, F ), suggesting that these might be the alloreactive clones that were rarely presented in pretransplant-donor T cells, but were highly expanded in response to alloantigen stimulation that might contribute to GVHD pathogenesis. In a clinical study of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors, rarefied and hyperexpanded clonotypic patterns were found to be the hallmarks of T-cell reconstitution and influenced clinical outcomes ( 17 ). By using CDR3-based specificity spectrum analysis, they found dominant expansion of pathogen- and tumor-associated clonotypes in the late post–allo-HCT phase, while autoreactive clones were more expanded in the case of GVHD occurrence.…”

Section: Discussionmentioning

confidence: 99%

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Wang

et al. 2021

Front. Immunol.

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The diversity and composition of T-cell receptor (TCR) repertoire, which is the result of V, (D), and J gene recombination in TCR gene locus, has been found to be implicated in T-cell responses in autoimmunity, cancer, and organ transplantation. The correlation of T-cell repertoire with the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation remains largely undefined. Here, by utilizing high-throughput sequencing of the genes encoding TCRβ-chain, we comprehensively analyzed the profile of T-cell repertoire in recipient lymphoid and GVHD target organs after bone marrow transplantation (BMT) in mice. In lymphoid organs, TCR diversity was narrowed, accompanied with reduced numbers of unique clones while increased accumulation of dominant clones in allogeneic T cells compared to syngeneic T cells. In an individual allogeneic recipient, donor-derived TCR clones were highly overlapped among tissue sites, and the degree of overlapping was increasing from day 7 to 14 after allogeneic BMT. The top clones in peripheral blood, gut, liver, and lungs were highly mutually shared in an allogenic recipient, indicating that blood has the potential to predict dominant clones in these GVHD target organs. T cells in GVHD target organs from allogeneic recipients had fewer overlapped clones with pre-transplant donor T cells compared to those from syngeneic recipients. Importantly, the top 10 clones in allogeneic recipients were not detectable in pre-transplant donor T cells, indicating clonal expansion of rare rearrangements. Interestingly, even starting from the same pool of donor repertoires, T cells had very few overlapped clones between each allogeneic recipient who developed completely different dominant clones. We were only able to trace a single clone shared by three replicate allogeneic recipients within the top 500 clones. Although dominant clones were different among allogeneic recipients, V26 genes were consistently used more frequently by TCR clones in allogeneic than syngeneic recipients. This is the first study to extensively examine the feature of T-cell repertoire in multiple lymphoid and parenchyma organs, which establishes the association between T-cell activation and GVHD pathogenesis at the level of TCR clones. Immune repertoire sequencing-based methods may represent a novel personalized strategy to guide diagnosis and therapy in GVHD.

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Section: Discussionmentioning

confidence: 99%

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Wang

et al. 2021

Front. Immunol.

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“…ImmunoSeq Analizer 3.0 suite was used for sample export and preliminary statistics and quality control steps while R Bioconductor 72 environment and Immunarch R 73 suite were used for all the downstream analyses as previously described (Supplementary Data 8). 21…”

Section: Hla Mutational Analysismentioning

confidence: 99%

“…20 Furthermore, we and others demonstrated that recipient HED correlates with the e ciency of immune reconstitution after allo-HCT. 21,22 Since this score mirrors the antigenic spectrum capacity, it may be considered a surrogate of the individuals' ability to present leukemia associated antigens (LAA) in transplant recipients. 20,23,24 In analogy with solid cancer immunotherapy, we hypothesized that, also in the context of allo-HCT, a reduced variability of HLA genotypes as well as genomic mechanisms of escape can converge in overlapping immune-escape phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Pagliuca

Gurnari

Hercus

et al. 2023

Preprint

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Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

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“…The study of the physiochemical composition of these motifs may be deployed to enhance binding prediction performance ( 55 ). In addition, characterization of complementarity determining 3 regions (CDR3) within the variable portion of TCR beta chains may be used to enhance reverse prediction of bound antigens ( 10 , 56 , 57 ). Theoretically one could predict the characteristics and the specificity of each epitope (i.e.…”

Section: Notes On Peptide Binding Predictionmentioning

confidence: 99%

Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

et al. 2022

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Structural and functional variability of human leukocyte antigen (HLA) is the foundation for competent adaptive immune responses against pathogen and tumor antigens as it assures the breadth of the presented immune-peptidome, theoretically sustaining an efficient and diverse T cell response. This variability is presumably the result of the continuous selection by pathogens, which over the course of evolution shaped the adaptive immune system favoring the assortment of a hyper-polymorphic HLA system able to elaborate efficient immune responses. Any genetic alteration affecting this diversity may lead to pathological processes, perturbing antigen presentation capabilities, T-cell reactivity and, to some extent, natural killer cell functionality. A highly variable germline HLA genotype can convey immunogenetic protection against infections, be associated with tumor surveillance or influence response to anti-neoplastic treatments. In contrast, somatic aberrations of HLA loci, rearranging the original germline configuration, theoretically decreasing its variability, can facilitate mechanisms of immune escape that promote tumor growth and immune resistance.The purpose of the present review is to provide a unified and up-to-date overview of the pathophysiological consequences related to the perturbations of the genomic heterogeneity of HLA complexes and their impact on human diseases, with a special focus on cancer.

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Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

Cited by 16 publications

References 41 publications

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

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