Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans

Gordin, Miri; Philip, Hagit; Zilberberg, Alona; Gidoni, Moriah; Margalit, Raanan; Clouser, Christopher R.; Adams, Kristofor; Vigneault, François; Cohen, Irun R.; Yaari, Gur; Efroni, Sol

doi:10.1371/journal.pcbi.1008486

Cited by 15 publications

(12 citation statements)

References 53 publications

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“…Instead of focusing on a specific TCR, one could propose to use more generic features of the repertoire to distinguish between CMV+ and CMV-patients ((46; 23; 43)). This may be true for lytic conditions, but not for latent or historical conditions.…”

Section: Resultsmentioning

confidence: 99%

Counting is Almost All You Need

Akerman

Louzoun

Isakov

et al. 2022

Preprint

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The immune memory repertoire encodes the history of present and past infections and immunological attributes of the individual. As such, multiple methods were proposed to use T-cell receptor (TCR) repertoires to detect disease history. We here show that the counting method outperforms all existing algorithms. We then show that the counting can be further improved using a novel attention model to weight the different TCRs. The attention model is based on the projection of TCRs using a Variational AutoEncoder (VAE). Both counting and attention algorithms predict better than any current algorithm whether the host had CMV and its HLA alleles. As an intermediate solution between the complex attention model and the very simple counting model, we propose a new Graph Convolutional Network approach that obtains the accuracy of the attention model and the simplicity of the counting model. The code for the models used in the paper is provided in: https://github.com/louzounlab/CountingIsAlmostAllYouNeed

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Section: Resultsmentioning

confidence: 99%

Counting is Almost All You Need

Akerman

Louzoun

Isakov

et al. 2022

Preprint

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“…Based on the criteria used in the TCR3d, we attempted to identify similar CDR3 sequences with substitution of 1 or 2 AA using the Levenshtein distance. 21 , 40 The Levenshtein distance, however, is a mathematical method of calculating the similarity of two sentences, but it does not take into account the biological similarities of AA. PAM or BLOSUM are more biologically oriented methods of assessing the similarity of AA.…”

Section: Discussionmentioning

confidence: 99%

Immune repertoire and responses to neoadjuvant TCHP therapy in HER2-positive breast cancer

Shin

Ham²,

Seo³

et al. 2023

Ther Adv Med Oncol

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Background: Despite the introduction of trastuzumab, pathologic complete response (pCR) is not attained in approximately 30–40% of Human epithelial growth factor receptor-2-positive breast cancer. Tumor-infiltrating lymphocytes (TIL) have been suggested as a predictive marker of treatment response, albeit not always effective. We investigated the relationship between trastuzumab, docetaxel, carboplatin, and pertuzumab (TCHP) treatment and immune repertoire as a treatment response predictor. Design: In all, 35 cases were divided into two experimental groups: 10 and 25 cases in the preliminary and main experiments, respectively. In the preliminary experiment, the biopsy tissues before TCHP treatment and the surgical tissues after TCHP treatment were compared. In the main experiment, the biopsy tissues before TCHP treatment were compared according to the TCHP treatment response. Methods: The T-cell repertoire for TRA, TRB, TRG, and TRD, and B-cell repertoire for immunoglobulin heavy, immunoglobulin kappa, and immunoglobulin lambda were evaluated. Whole transcriptome sequencing was also performed. Results: In the preliminary experiment, the density and richness of the T-cell receptor (TCR) and B-cell receptor (BCR) repertoires decreased after treatment, regardless of TCHP response. In the main experiment, the Shannon’s entropy index, density, and length of CDR3 of the TCR and BCR repertoires did not differ significantly in patients who did and did not achieve pCR. The pCR and non-pCR subgroups according to the level of TILs revealed that the non-pCR/lowTIL group had a higher proportion of low-frequency clones than the pCR/lowTIL group in TRA (non-pCR/lowTIL versus pCR/lowTIL, 0.01–0.1%, 63% versus 45.3%; <0.01%, 32.9% versus 51.8%, p < 0.001) and TRB (non-pCR/lowTIL versus pCR/lowTIL, 0.01–0.1%, 26.5% versus 14.7%; <0.01%, 72.0% versus 84.1%, p < 0.001). Conclusions: The role of the diversity, richness, and density of the TCR and BCR repertoires as predictive markers for TCHP response was not identified. Compositions of low-frequency clones could be candidates for predictive factors of TCHP response; however, validation studies and further research are necessary.

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“…Specific V and J (in either α or β chains) were shown to differ between diseases ( 15 , 16 ). A study from 2017 provides evidence for TCR expansion of clonotypes in autoreactive CD8+ T cells associated with type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…We show in human donors and mice a clear bias towards specific V b J b combinations that are more frequent than expected from the V b and J b probabilities in both CD4 and CD8 T cells. Specific V and J (in either a or b chains) were shown to differ between diseases (15,16). A study from 2017 provides evidence for TCR expansion of clonotypes in autoreactive CD8+ T cells associated with type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Two Step Selection for Bias in β Chain V-J Pairing

Levi

Louzoun

2022

Front. Immunol.

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The β chain rearrangement in T cells is a two-step process where first Dβ and Jβ bind, and only then Vβ is joined to the complex. We here show that the frequency of human and mouse Vβ Jβ combinations deviates from the one expected based on each gene usage frequency. This bias is observed mainly in functional (F) rearrangements, but also slightly in non-functional (NF) rearrangements. Preferred Vβ Jβ combinations in F clones are shared between donors and samples, suggesting a common structural mechanism for these biases in addition to any host-specific antigen-induced peripheral selection. The sharing holds even in clones with Jβ1 that share the same Dβ1 gene. Vβ Jβ usage is correlated with the Molecular Weight and Isoelectric Point in F clones. The pairing is also observed in the Double Positive cells in mice thymocytes, suggesting that the selection leading to such a pairing occurs before thymic selection. These results suggest an additional structural checkpoint in the beta chain development prior to thymic selection during the T cell receptor expression. Understanding this structural selection is important for the distinction between normal and aberrant T cell development, and crucial for the design of engineered TCRs.

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Breast cancer is marked by specific, Public T-cell receptor CDR3 regions shared by mice and humans

Cited by 15 publications

References 53 publications

Counting is Almost All You Need

Counting is Almost All You Need

Immune repertoire and responses to neoadjuvant TCHP therapy in HER2-positive breast cancer

Two Step Selection for Bias in β Chain V-J Pairing

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