BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells

Abstract

Highlights d BTN2A1 expression in cancer cells correlates with Vg9Vd2 T cell cytotoxicity d BTN2A1 interacts with BTN3A1/3A2/3A3, leading to enhanced plasma membrane export d B30.2 domains of both BTN3A1 and BTN2A1 are required for pAg responsiveness d Anti-BTN2A1 mAbs blocking Vg9Vd2TCR binding antagonize Vg9Vd2 T cell cytotoxicity

Strategies to Improve the Antitumor Effect of γδ T Cell Immunotherapy for Clinical Application

“…BTN2A1 interacts with BTN3A1, leading to enhance plasma membrane export, and BTN2A1/BTN3A1 interaction is enhanced by PAgs. Anti-BTN2A monoclonal antibodies (mAbs) inhibit BTN2A1 biding to the γδ TCR and modulate γδ T cell killing of cancer cells [21]. These studies demonstrate the potential of butyrophilin subfamily cooperation pathway as a therapeutic target in γδ T cell activation.…”

“…The precise mechanism by which γδ T cells recognize BTN3A1 is not completely clear, but several studies demonstrate that binding of PAgs directly to a positively-charged pocket in the intracellular B30.2 domain of BTN3A1 recruits the cytoskeletal adaptor protein periplakin and the GTPase RhoB, which increases membrane mobility and induces a conformational change in BTN3A1; the altered conformation is recognized by the γδ TCR [18,19]. Recent studies show that BTN2A1, which binds directly to the TCRs via germline-encoded regions of Vγ9, is also essential to BTN3A-mediated γδ T cell cytotoxicity and BTN2A1 expression at the plasma membrane of cancer cells correlated with γδ T cell cytotoxicity [20,21]. BTN2A1 interacts with BTN3A1, leading to enhance plasma membrane export, and BTN2A1/BTN3A1 interaction is enhanced by PAgs.…”

PD-1 checkpoint blockade enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against human prostate cancer

“…Both BTN3A1 and BTN2A1 are expressed by all malignant human cells tested, 9 allowing Vγ2Vδ2 T cells to recognize and kill tumor cells with altered isoprenoid metabolism, either through pharmacological manipulation by aminobisphosphonate drugs, such as pamidronate or zoledronic acid, 10 or through undefined defects, such as those present in some B cell tumors such as Daudi, 11 RPMI 8226, 12 and XG-7. [13][14][15] Vγ2Vδ2 TCR stimulation by these tumor cells is clearly mediated by BTN3A1 14 and BTN2A1 15 . A number of different alterations in endogenous isoprenoid metabolism such as overexpression of HMG-CoA reductase, 16 inhibition of FDPS or isopentenyl diphosphate isomerase through siRNA/shRNA treatment, 10,17 or addition of the rate limiting metabolite, mevalonate 10 can convert tumor cells into activators for Vγ2Vδ2 T cells.…”

Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More

“…It contains protein-encoding genes ( 7 ). Four of them; BTN2A1, BTN3A1 (CD277), BTN3A2 and BTN3A3, contribute to γδ T cell activation ( 8 – 13 ). While BTN3 genes first emerged in placental mammals ( 14 ) BTN1 and BTN2 genes co-emerged with the evolvement of vertebrates ( 7 ).…”