BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells

Payne, Kyle K.; Mine, Jessica A.; Biswas, Subir; Chaurio, Ricardo A.; Perales‐Puchalt, Alfredo; Anadon, Carmen M.; Costich, Tara Lee; Harro, Carly M.; Walrath, Jennifer; Ming, Qianqian; Tcyganov, Evgenii N.; Buras, Andrea; Rigolizzo, Kristen E.; Mandal, Gunjan; Lajoie, Jason; Ophir, Michael; Tchou, Julia; Marchion, Douglas C.; Luca, Vincent C.; Bobrowicz, Piotr; McLaughlin, Brooke M.; Eskiocak, Uğur; Schmidt, Michael M.; Cubillos-Ruiz, Juan R.; Rodríguez, Paulo C.; Gabrilovich, Dmitry I.; Conejo-Garcia, José R.

doi:10.1126/science.aay2767

Cited by 92 publications

(118 citation statements)

References 43 publications

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“…Indeed, intratumoral γδ T cells have emerged as the most significant favorable cancer-wide prognostic infiltrating immune subset, and γδ T-cell-based clinical trials are increasingly performed, expanding our portfolio of immunotherapeutical approaches ( Gentles et al., 2015 ). In addition to its role in the activation of γ δ T cells, recent findings illustrate how BTN3A1 can play an inhibitory function on αβ T cells, by hindering the segregation of the phosphatase CD45 from the immune synapse ( Payne et al., 2020 ). Importantly, this inhibition is relieved upon zoledronate treatment or by the use of CD277-specific agonistic antibodies, which enable the concomitant activation of V γ 9V δ 2 T cells.…”

Section: Discussionmentioning

confidence: 99%

NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

et al. 2021

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Summary BTN3A molecules—BTN3A1 in particular—emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis -infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.

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Section: Discussionmentioning

confidence: 99%

NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

et al. 2021

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“…Ovarian cancer is an immunogenic disease in which the pre-established immunoreactive landscape determines the outcome of the patient 1 – 3 , 7 . However, as monotherapies such as immune checkpoint inhibitors that augment T cell activity have only very modest response rates in patients with advanced disease 4 .…”

Section: Mainmentioning

confidence: 99%

IgA transcytosis and antigen recognition govern ovarian cancer immunity

Biswas

Mandal

Payne

et al. 2021

Nature

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114

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Most ovarian cancers are infiltrated by prognostically relevant activated T cells1–3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

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“…The mechanism for recognizing pAgs is not yet clear, although several studies have recently expanded the information about how γδ T cells identify these molecules. Recent reports have pointed out that pAgs recognition is mediated by BTN-like molecules, which are expressed in cancer cells [ 72 , 75 ] and are able to modulate the responses of conventional αβ T cells [ 76 – 79 ], and most notably, of γδ T cells [ 68 – 71 , 80 , 81 ]. The dependent detection of pAgs by V γ 9V δ 2 cells involves the entire structure of the TCR, which interacts with BTN molecules through the V γ 9 and V δ 2 TCR domains.…”

Section: Subsets Of Unconventional T Cells In Antileukemic Responsmentioning

confidence: 99%

Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity

Araújo

Barros

Ribeiro

et al. 2021

Journal of Immunology Research

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Recently, cell-mediated immune response in malignant neoplasms has become the focus in immunotherapy against cancer. However, in leukemia, most studies on the cytotoxic potential of T cells have concentrated only on T cells that recognize peptide antigens (Ag) presented by polymorphic molecules of the major histocompatibility complex (MHC). This ignores the great potential of unconventional T cell populations, which include gamma-delta T cells (γδ), natural killer T cells (NKT), and mucosal-associated invariant T cells (MAIT). Collectively, these T cell populations can recognize lipid antigens, specially modified peptides and small molecule metabolites, in addition to having several other advantages, which can provide more effective applications in cancer immunotherapy. In recent years, these cell populations have been associated with a repertoire of anti- or protumor responses and play important roles in the dynamics of solid tumors and hematological malignancies, thus, encouraging the development of new investigations in the area. This review focuses on the current knowledge regarding the role of unconventional T cell populations in the antitumor immune response in leukemia and discusses why further studies on the immunotherapeutic potential of these cells are needed.

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BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells

Cited by 92 publications

References 43 publications

NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing

IgA transcytosis and antigen recognition govern ovarian cancer immunity

Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity

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