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T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

ABSTRACT: Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

SUBMITTER: Ali M

PROVIDER: S-EPMC9005346 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Ali Muhammad M Giannakopoulou Eirini E Li Yingqian Y Lehander Madeleine M Virding Culleton Stina S Yang Weiwen W Knetter Cathrine C Odabasi Mete Can MC Bollineni Ravi Chand RC Yang Xinbo X Foldvari Zsofia Z Böschen Maxi-Lu ML Taraldsrud Eli E Strønen Erlend E Toebes Mireille M Hillen Amy A Mazzi Stefania S de Ru Arnoud H AH Janssen George M C GMC Kolstad Arne A Tjønnfjord Geir Erland GE Lie Benedicte A BA Griffioen Marieke M Lehmann Sören S Osnes Liv Toril LT Buechner Jochen J Garcia K Christopher KC Schumacher Ton N TN van Veelen Peter A PA Leisegang Matthias M Jacobsen Sten Eirik W SEW Woll Petter P Olweus Johanna J

Nature biotechnology 20211206 4

Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated ...[more]

PMID: 34873326

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Project description:UnlabelledCD56+ natural killer (NK) and CD56+ T cells, from sputum or bronchoalveolar lavage of subjects with chronic obstructive pulmonary disease (COPD) are more cytotoxic to highly susceptible NK targets than those from control subjects. Whether the same is true in lung parenchyma, and if NK activity actually contributes to emphysema progression are unknown. To address these questions, we performed two types of experiments on lung tissue from clinically-indicated resections (n = 60). First, we used flow cytometry on fresh single-cell suspension to measure expression of cell-surface molecules (CD56, CD16, CD8, NKG2D and NKp44) on lung lymphocytes and of the 6D4 epitope common to MICA and MICB on lung epithelial (CD326+) cells. Second, we sequentially isolated CD56+, CD8+ and CD4+ lung lymphocytes, co-cultured each with autologous lung target cells, then determined apoptosis of individual target cells using Annexin-V and 7-AAD staining. Lung NK cells (CD56+ CD3-) and CD56+ T cells (CD56+ CD3+) were present in a range of frequencies that did not differ significantly between smokers without COPD and subjects with COPD. Lung NK cells had a predominantly "cytotoxic" CD56+ CD16+ phenotype; their co-expression of CD8 was common, but the percentage expressing CD8 fell as FEV1 % predicted decreased. Greater expression by autologous lung epithelial cells of the NKG2D ligands, MICA/MICB, but not expression by lung CD56+ cells of the activating receptor NKG2D, correlated inversely with FEV1 % predicted. Lung CD56+ lymphocytes, but not CD4+ or CD8+ conventional lung T cells, rapidly killed autologous lung cells without additional stimulation. Such natural cytotoxicity was increased in subjects with severe COPD and was unexplained in multiple regression analysis by age or cancer as indication for surgery. These data show that as spirometry worsens in COPD, CD56+ lung lymphocytes exhibit spontaneous cytotoxicity of autologous structural lung cells, supporting their potential role in emphysema progression.Trial registrationClinicalTrials.gov NCT00281229.

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T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

Publications

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.

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