γ9δ2 T-Cell Expansion and Phenotypic Profile Are Reflected in the CDR3δ Repertoire of Healthy Adults

Vyborova, Anna; Janssen, Anke; Gatti, Lucrezia C D E; Karaiskaki, Froso; Yonika, Austin; Dooremalen, Sanne van; Sanders, Jasper; Beringer, Dennis X.; Straetemans, Trudy; Sebestyén, Zsolt; Kuball, Jürgen

doi:10.3389/fimmu.2022.915366

Cited by 2 publications

(1 citation statement)

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“…In vitro Vγ9δ2T cells recognize and lyse a broad spectrum of solid and hematological tumor cells ( 21 , 22 ) and therefore provide an interesting tool box for the development of anti-cancer therapies ( 23 ). However, the activity of Vγ9δ2T cells is diverse when analyzed in a clonal population ( 17 ), and can be hampered by many inhibitory receptors, like NKG2A ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

The making of multivalent gamma delta TCR anti-CD3 bispecific T cell engagers

Diest

Nicolasen²,

Kramer³

et al. 2023

Front. Immunol.

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IntroductionWe have recently developed a novel T cell engager concept by utilizing γ9δ2TCR as tumor targeting domain, named gamma delta TCR anti-CD3 bispecific molecule (GAB), targeting the phosphoantigen-dependent orchestration of BTN2A1 and BTN3A1 at the surface of cancer cells. GABs are made by the fusion of the ectodomains of a γδTCR to an anti-CD3 single chain variable fragment (scFv) (γδECTO-αCD3), here we explore alternative designs with the aim to enhance GAB effectivity.MethodsThe first alternative design was made by linking the variable domains of the γ and δ chain to an anti-CD3 scFv (γδVAR-αCD3). The second alternative design was multimerizing γδVAR-αCD3 proteins to increase the tumor binding valency. Both designs were expressed and purified and the potency to target tumor cells by T cells of the alternative designs was compared to γδECTO-αCD3, in T cell activation and cytotoxicity assays.Results and discussionThe γδVAR-αCD3 proteins were poorly expressed, and while the addition of stabilizing mutations based on finding for αβ single chain formats increased expression, generation of meaningful amounts of γδVAR-αCD3 protein was not possible. As an alternative strategy, we explored the natural properties of the original GAB design (γδECTO-αCD3), and observed the spontaneous formation of γδECTO-αCD3-monomers and -dimers during expression. We successfully enhanced the fraction of γδECTO-αCD3-dimers by shortening the linker length between the heavy and light chain in the anti-CD3 scFv, though this also decreased protein yield by 50%. Finally, we formally demonstrated with purified γδECTO-αCD3-dimers and -monomers, that γδECTO-αCD3-dimers are superior in function when compared to similar concentrations of monomers, and do not induce T cell activation without simultaneous tumor engagement. In conclusion, a γδECTO-αCD3-dimer based GAB design has great potential, though protein production needs to be further optimized before preclinical and clinical testing.

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Section: Introductionmentioning

confidence: 99%

The making of multivalent gamma delta TCR anti-CD3 bispecific T cell engagers

Diest

Nicolasen²,

Kramer³

et al. 2023

Front. Immunol.

Self Cite

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Progress of research on γδ T cells in colorectal cancer (Review)

Pan,

Zhou,

Kuang

et al. 2024

Oncol Rep

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Colorectal cancer (CRC) ranks as the third most prevalent malignancy and second leading cause of cancer-related fatalities worldwide. Immunotherapy alone or in combination with chemotherapy has a favorable survival benefit for patients with CRC. Unlike αβ T cells, which are prone to drug resistance, γδ T cells do not exhibit major histocompatibility complex restriction and can target tumor cells through diverse mechanisms. Recent research has demonstrated the widespread involvement of Vδ1T, Vδ2T, and γδ T17 cells in tumorigenesis and progression. In the present review, the influence of different factors, including immune checkpoint molecules, the tumor microenvironment and microorganisms, was summarized on the antitumor/protumor effects of these cells, aiming to provide insights for the development of more efficient and less toxic immunotherapy-based anticancer drugs.

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γ9δ2 T-Cell Expansion and Phenotypic Profile Are Reflected in the CDR3δ Repertoire of Healthy Adults

Cited by 2 publications

References 52 publications

The making of multivalent gamma delta TCR anti-CD3 bispecific T cell engagers

The making of multivalent gamma delta TCR anti-CD3 bispecific T cell engagers

Progress of research on γδ T cells in colorectal cancer (Review)

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