NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions

Cazzetta, Valentina; Bruni, Elena; Terzoli, Sara; Carenza, Claudia; Franzese, Sara; Marzano, Paolo; Donadon, Matteo; Torzilli, Guido; Cimino, Matteo; Simonelli, Matteo; Bello, Lorenzo; Villa, Anna; Tan, Likai; Ravens, Sarina; Prinz, Immo; Supino, Domenico; Colombo, Federico; Lugli, Enrico; Marcenaro, Emanuela; Vivier, Éric; Bella, Silvia Della; Mikulak, Joanna; Mavilio, Domenico

doi:10.1016/j.celrep.2021.109871

Cited by 48 publications

(56 citation statements)

References 71 publications

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“…Although we did not find compelling evidence for skewing in NKG2D expression toward putative pAg-unreactive clones, there could be still an effect of the signal strength through the γδTCR, generally considered “signal one” ( 44 ), on the landscape of the remaining NKRs and thus on the net NKR signal. We therefore aimed to investigate the TCR repertoire features in the context of surface expression of CD94/NKG2A(B), an inhibitory C-type lectin receptor broadly expressed on the γ9δ2T cells and recently reported to identify a highly pAg- and tumor-reactive γ9δ2T cell subset ( 45 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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γ9δ2T cells fill a distinct niche in human immunity due to the unique physiology of the phosphoantigen-reactive γ9δ2TCR. Here, we highlight reproducible TCRδ complementarity-determining region 3 (CDR3δ) repertoire patterns associated with γ9δ2T cell proliferation and phenotype, thus providing evidence for the role of the CDR3δ in modulating in vivo T-cell responses. Features that determine γ9δ2TCR binding affinity and reactivity to the phosphoantigen-induced ligand in vitro appear to similarly underpin in vivo clonotypic expansion and differentiation. Likewise, we identify a CDR3δ bias in the γ9δ2T cell natural killer receptor (NKR) landscape. While expression of the inhibitory receptor CD94/NKG2A is skewed toward cells bearing putative high-affinity TCRs, the activating receptor NKG2D is expressed independently of the phosphoantigen-sensing determinants, suggesting a higher net NKR activating signal in T cells with TCRs of low affinity. This study establishes consistent repertoire–phenotype associations and justifies stratification for the T-cell phenotype in future research on γ9δ2TCR repertoire dynamics.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…CD159α (NKG2A), which was found on expanded γδ T and NK cells across all donors, is classically considered an inhibitory receptor for NK, NK T, and CD8 + αβ T cells; 40 , 41 however, recently, constitutive expression of NKG2A on Vδ2 T lymphocytes has been associated with a subset of γδ T cells licensed with potent cytotoxic effector function and hyper-responsive anti-tumor activity. 42 High expression of CD95 (FAS receptor) was also observed among expanded cells (γδ T > NK). While FAS expression on expanded γδ T/NK cells could be a setup for autocrine activation and fratricide given expanded γδ T cells and NK cells also expressed its activating ligand, FasL, our current findings do not support that this limits expansion, persistence, or cytotoxic potential.…”

Section: Discussionmentioning

confidence: 98%

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

Jonus

Burnham

et al. 2022

OncoImmunology

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γδ T lymphocytes represent an emerging class of cellular immunotherapy with preclinical promise to treat cancer, notably neuroblastoma. The innate-like immune cell subset demonstrates inherent cytoxicity toward tumor cells independent of MHC recognition, enabling allogeneic administration of healthy donor-derived γδ T cell therapies. A current limitation is the substantial interindividual γδ T cell expansion variation among leukocyte collections. Overcoming this limitation will enable realization of the full potential of allogeneic γδ T-based cellular therapy. Here, we characterize γδ T cell expansions from healthy adult donors and observe that highly potent natural killer (NK) lymphocytes expand with γδ T cells under zoledronate and IL-2 stimulation. The presence of NK cells correlates with both the expansion potential of γδ T cells and the overall potency of the γδ T cell therapy. However, the potency of the cell therapy in combination with an antibody-based immunotherapeutic, dinutuximab, appears to be independent of γδ T/NK cell content both in vitro and in vivo , which minimizes the implication of interindividual expansion differences toward efficacy. Collectively, these studies highlight the utility of maintaining the NK cell population within expanded γδ T cell therapies and suggest a synergistic action of combined innate cell immunotherapy toward neuroblastoma.

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“…68 Recently, expression of NKG2A has been described on a subset of peripheral blood Vδ2 T cells in which effector function upon activation was higher in comparison to that of the NKG2Anegative subset. 77 In the same study, after the IL-2/Zol expansion of Vδ2 T cells, NKG2A expression was maintained and correlated with higher cytotoxicity, higher cytokine production, and a transcriptional profile enriched in immune-regulation and antitumor response signaling pathways. Furthermore, tumor-infiltrating Vδ2 T cells expressed high levels of NKG2A, and their cytotoxicity was fine-tuned by the presence of HLA-E, an inhibitory ligand of NKG2A.…”

Section: Considerations For Production Of γδ T-cell-based Act Productmentioning

confidence: 90%

“…It seems that hyperresponding NKG2A-expressing Vγ9Vδ2 T cells may have superior antitumor effect as ACT against HLA-E-low or HLA-E-negative tumors. 77 CD56 and CD161 have also been associated with increased cytotoxic potential and cytokine production. [78][79][80] Stimulation with IL-15 drives increased expression of CD56, 67 whereas IL-12 and IL-18 stimulation was associated with greater expression of CD161.…”

Section: Considerations For Production Of γδ T-cell-based Act Productmentioning

confidence: 99%

“…80 Interestingly, expression of NKG2A negatively correlated with CD161, whereas there was no significant correlation between NKG2A and CD56 or NKG2D. 77 Thus, more work is required to define the best markers that will represent more potent γδ T-cell populations for ACT. Another factor that could improve γδ T-cell-based ACTs is understanding the role of immune checkpoints in their regulation and antitumor response.…”

Section: Considerations For Production Of γδ T-cell-based Act Productmentioning

confidence: 99%

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γδ T Cell–Based Adoptive Cell Therapies Against Solid Epithelial Tumors

Bustos¹,

Snedal²,

Tordesillas³

et al. 2022

Cancer J

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Conventionally, adoptive cell therapies have been developed and optimized using αβ T cells. However, the understudied and less abundant γδ T cells offer unique advantages to the immunotherapy field especially for therapies against solid tumors. Recently, γδ T-cell potential against a broad spectrum of malignant cells has been demonstrated in the preclinical setting. In the clinic, γδ T-cell-based immunotherapies have proven to be safe; however, their efficacy needs improvement. Considering the growing body of literature reflecting the increasing interest in γδ T cells, we sought to capture the current topics of discussion in the field, pertaining to their use in adoptive immunotherapy. We aimed to compile information about γδ T-cell enhancement in terms of expansion, phenotype, and inhibitory receptors, in addition to the latest advances in preclinical and clinical research using γδ T cells specifically against solid epithelial tumors.

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NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions

Cited by 48 publications

References 71 publications

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

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

Dissecting the cellular components of ex vivo γδ T cell expansions to optimize selection of potent cell therapy donors for neuroblastoma immunotherapy trials

γδ T Cell–Based Adoptive Cell Therapies Against Solid Epithelial Tumors

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