Targeting solid tumors via T cell receptor complementarity-determining region 3δ in an engineered antibody

The bottlenose dolphin (Tursiops truncatus) belongs to the Cetartiodactyla and, similarly to other cetaceans, represents the most successful mammalian colonization of the aquatic environment. Here we report a genomic, evolutionary, and expression study of T. truncatus T cell receptor beta (TRB) genes. Although the organization of the dolphin TRB locus is similar to that of the other artiodactyl species, with three in tandem D-J-C clusters located at its 3′ end, its uniqueness is given by the reduction of the total length due essentially to the absence of duplications and to the deletions that have drastically reduced the number of the germline TRBV genes. We have analyzed the relevant mature transcripts from two subjects. The simultaneous availability of rearranged T cell receptor α (TRA) and TRB cDNA from the peripheral blood of one of the two specimens, and the human/dolphin amino acids multi-sequence alignments, allowed us to calculate the most likely interactions at the protein interface between the alpha/beta heterodimer in complex with major histocompatibility class I (MH1) protein. Interacting amino acids located in the complementarity-determining region according to IMGT numbering (CDR-IMGT) of the dolphin variable V-alpha and beta domains were identified. According to comparative modelization, the atom pair contact sites analysis between the human MH1 grove (G) domains and the T cell receptor (TR) V domains confirms conservation of the structure of the dolphin TR/pMH.

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Composition and Variation Analysis of the T Cell Receptor β -Chain Complementarity Determining Region 3 Repertoire in Neonatal Sepsis

Scandinavian Journal of Immunology ◽

10.1111/sji.12614 ◽

2017 ◽

Vol 86 (5) ◽

pp. 418-423 ◽

Cited By ~ 3

Author(s):

J. Sun ◽

B. Sun ◽

Y. Gao ◽

F. He ◽

L. Yang ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Neonatal Sepsis ◽

Cell Receptor ◽

Variation Analysis ◽

Β Chain ◽

Complementarity Determining Region

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The correlation between ovomucoid-derived peptides, human leucocyte antigen class II molecules and T cell receptor-complementarity determining region 3 compositions in patients with egg-white allergy

Clinical & Experimental Allergy ◽

10.1046/j.1365-2745.2002.01433.x ◽

2002 ◽

Vol 32 (8) ◽

pp. 1223-1230 ◽

Cited By ~ 6

Author(s):

K. Suzuki ◽

R. Inoue ◽

H. Sakaguchi ◽

M. Aoki ◽

Z. Kato ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Human Leucocyte Antigen ◽

Cell Receptor ◽

Class Ii ◽

Egg White ◽

Human Leucocyte Antigen Class ◽

Complementarity Determining Region

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Conserved T Cell Receptor Complementarity-Determining Region 3 of Ocular T Cells in Mice with Experimental Autoimmune Uveoretinitis

Ophthalmic Research ◽

10.1159/000055544 ◽

1999 ◽

Vol 31 (4) ◽

pp. 249-255 ◽

Cited By ~ 1

Author(s):

Reiko Uehara ◽

Koushi Fujisawa ◽

Takeshi Kezuka ◽

Jun-Ichi Sakai ◽

Kusuki Nishioka ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Experimental Autoimmune Uveoretinitis ◽

Complementarity Determining Region ◽

Experimental Autoimmune

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Atypical TRAV1-2− T cell receptor recognition of the antigen-presenting molecule MR1

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015292 ◽

2020 ◽

Vol 295 (42) ◽

pp. 14445-14457 ◽

Cited By ~ 1

Author(s):

Wael Awad ◽

Erin W. Meermeier ◽

Maria L. Sandoval-Romero ◽

Jérôme Le Nours ◽

Aneta H. Worley ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Mait Cells ◽

Receptor Recognition ◽

Antigen Presenting ◽

Β Chain ◽

Complementarity Determining Region

MR1 presents vitamin B–related metabolites to mucosal associated invariant T (MAIT) cells, which are characterized, in part, by the TRAV1-2+ αβ T cell receptor (TCR). In addition, a more diverse TRAV1-2− MR1-restricted T cell repertoire exists that can possess altered specificity for MR1 antigens. However, the molecular basis of how such TRAV1-2− TCRs interact with MR1–antigen complexes remains unclear. Here, we describe how a TRAV12-2+ TCR (termed D462-E4) recognizes an MR1–antigen complex. We report the crystal structures of the unliganded D462-E4 TCR and its complex with MR1 presenting the riboflavin-based antigen 5-OP-RU. Here, the TRBV29-1 β-chain of the D462-E4 TCR binds over the F′-pocket of MR1, whereby the complementarity-determining region (CDR) 3β loop surrounded and projected into the F′-pocket. Nevertheless, the CDR3β loop anchored proximal to the MR1 A′-pocket and mediated direct contact with the 5-OP-RU antigen. The D462-E4 TCR footprint on MR1 contrasted that of the TRAV1-2+ and TRAV36+ TCRs' docking topologies on MR1. Accordingly, diverse MR1-restricted T cell repertoire reveals differential docking modalities on MR1, thus providing greater scope for differing antigen specificities.

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Interaction among human leucocyte antigen-peptide-T cell receptor complexes in cow's milk allergy: the significance of human leucocyte antigen and T cell receptor-complementarity determining region 3 loops

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.2002.01370.x ◽

2002 ◽

Vol 32 (5) ◽

pp. 762-770 ◽

Cited By ~ 22

Author(s):

H. Sakaguchi ◽

R. Inoue ◽

H. Kaneko ◽

M. Watanabe ◽

K. Suzuki ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Human Leucocyte Antigen ◽

Cell Receptor ◽

Cow’S Milk ◽

Milk Allergy ◽

Receptor Complexes ◽

Peptide T ◽

Antigen Peptide ◽

Complementarity Determining Region

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Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.aaz6667 ◽

2020 ◽

Vol 12 (571) ◽

pp. eaaz6667

Author(s):

Meixi Hao ◽

Siyuan Hou ◽

Weishuo Li ◽

Kaiming Li ◽

Lingjing Xue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Surface ◽

Cell Therapy ◽

Solid Tumors ◽

T Cell Receptor ◽

Chimeric Antigen Receptor ◽

Cell Receptor ◽

T Cell Therapy ◽

Engineered T Cells

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

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The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review

Technology in Cancer Research & Treatment ◽

10.1177/1533033819831068 ◽

2019 ◽

Vol 18 ◽

pp. 153303381983106 ◽

Cited By ~ 29

Author(s):

Jianxiang Zhang ◽

Lingyu Wang

Keyword(s):

Clinical Trials ◽

T Cell ◽

Cell Therapy ◽

Solid Tumors ◽

T Cell Receptor ◽

Chimeric Antigen Receptor ◽

Hematological Malignancies ◽

Antigen Receptor ◽

Cell Receptor ◽

T Cell Therapy

T-cell receptor–engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor–engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor–engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor–engineered T-cell therapy’s high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor–engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor’s affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor–engineered T-cell therapy due to tumor microenvironment were also discussed here.

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