BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells

K. K. Payne; J. A. Mine; S. Biswas; R. A. Chaurio; A. Perales-Puchalt; C. M. Anadon; T. L. Costich; C. M. Harro; J. Walrath; Q. Ming; E. Tcyganov; A. L. Buras; K. E. Rigolizzo; G. Mandal; J. Lajoie; M. Ophir; J. Tchou; D. Marchion; V. C. Luca; P. Bobrowicz; B. McLaughlin; U. Eskiocak; M. Schmidt; J. R. Cubillos-Ruiz; P. C. Rodriguez; D. I. Gabrilovich; J. R. Conejo-Garcia

doi:10.1126/science.aay2767

BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells

K. K. Payne, J. A. Mine, S. Biswas, R. A. Chaurio, A. Perales-Puchalt, C. M. Anadon, T. L. Costich, C. M. Harro, J. Walrath, Q. Ming, E. Tcyganov, A. L. Buras, K. E. Rigolizzo, G. Mandal, J. Lajoie, M. Ophir, J. Tchou, D. Marchion, V. C. Luca, P. BobrowiczB. McLaughlin, U. Eskiocak, M. Schmidt, J. R. Cubillos-Ruiz, P. C. Rodriguez, D. I. Gabrilovich, J. R. Conejo-Garcia

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

Gamma delta (gammadelta) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of gammadelta T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate alphabeta and gammadelta T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive alphabeta T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of alphabeta T cell effector activity and BTN2A1-dependent gammadelta lymphocyte cytotoxicity against BTN3A1(+) cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by alphabeta and gammadelta T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

Original language	American English
Pages (from-to)	942-949
Number of pages	8
Journal	Science
Volume	369
Issue number	6506
DOIs	https://doi.org/10.1126/science.aay2767
State	Published - 2020
Externally published	Yes

Keywords

Animals Antibodies, Monoclonal/therapeutic use Antigens, CD/genetics/*immunology Butyrophilins/*antagonists & inhibitors/genetics/*immunology Female Humans Immunotherapy/methods Intraepithelial Lymphocytes/*immunology Mice Mice, Transgenic Ovarian Neoplasms/*immunology/*therapy Receptors, Antigen, T-Cell, alpha-beta/immunology Tumor Cells, Cultured Xenograft Model Antitumor Assays

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/science.aay2767

https://www.ncbi.nlm.nih.gov/pubmed/32820120

Cite this

Payne, K. K., Mine, J. A., Biswas, S., Chaurio, R. A., Perales-Puchalt, A., Anadon, C. M., Costich, T. L., Harro, C. M., Walrath, J., Ming, Q., Tcyganov, E., Buras, A. L., Rigolizzo, K. E., Mandal, G., Lajoie, J., Ophir, M., Tchou, J., Marchion, D., Luca, V. C., ... Conejo-Garcia, J. R. (2020). BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells. Science, 369(6506), 942-949. https://doi.org/10.1126/science.aay2767

@article{6cf67aa3037e4412b4a380a77bcf2bda,

title = "BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells",

abstract = "Gamma delta (gammadelta) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of gammadelta T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate alphabeta and gammadelta T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive alphabeta T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of alphabeta T cell effector activity and BTN2A1-dependent gammadelta lymphocyte cytotoxicity against BTN3A1(+) cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by alphabeta and gammadelta T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.",

keywords = "Animals Antibodies, Monoclonal/therapeutic use Antigens, CD/genetics/*immunology Butyrophilins/*antagonists & inhibitors/genetics/*immunology Female Humans Immunotherapy/methods Intraepithelial Lymphocytes/*immunology Mice Mice, Transgenic Ovarian Neoplasms/*immunology/*therapy Receptors, Antigen, T-Cell, alpha-beta/immunology Tumor Cells, Cultured Xenograft Model Antitumor Assays",

author = "Payne, {K. K.} and Mine, {J. A.} and S. Biswas and Chaurio, {R. A.} and A. Perales-Puchalt and Anadon, {C. M.} and Costich, {T. L.} and Harro, {C. M.} and J. Walrath and Q. Ming and E. Tcyganov and Buras, {A. L.} and Rigolizzo, {K. E.} and G. Mandal and J. Lajoie and M. Ophir and J. Tchou and D. Marchion and Luca, {V. C.} and P. Bobrowicz and B. McLaughlin and U. Eskiocak and M. Schmidt and Cubillos-Ruiz, {J. R.} and Rodriguez, {P. C.} and Gabrilovich, {D. I.} and Conejo-Garcia, {J. R.}",

note = "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 Buras, Andrea L Rigolizzo, Kristen E Mandal, Gunjan Lajoie, Jason Ophir, Michael Tchou, Julia Marchion, Douglas Luca, Vincent C Bobrowicz, Piotr McLaughlin, Brooke Eskiocak, Ugur Schmidt, Michael Cubillos-Ruiz, Juan R Rodriguez, Paulo C Gabrilovich, Dmitry I Conejo-Garcia, Jose R eng U01 CA232758/CA/NCI NIH HHS/ P30 CA010815/CA/NCI NIH HHS/ T32 CA009140/CA/NCI NIH HHS/ R01 CA211913/CA/NCI NIH HHS/ R01 CA240434/CA/NCI NIH HHS/ R01 CA157664/CA/NCI NIH HHS/ R01 NS114653/NS/NINDS NIH HHS/ R01 CA178687/CA/NCI NIH HHS/ P30 CA076292/CA/NCI NIH HHS/ R21 CA248106/CA/NCI NIH HHS/ R01 CA124515/CA/NCI NIH HHS/ R01 CA184185/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2020/08/21 Science. 2020 Aug 21;369(6506):942-949. doi: 10.1126/science.aay2767.",

year = "2020",

doi = "10.1126/science.aay2767",

language = "American English",

volume = "369",

pages = "942--949",

journal = "Science",

issn = "1095-9203",

publisher = "American Association for the Advancement of Science",

number = "6506",

}

Payne, KK, Mine, JA, Biswas, S, Chaurio, RA, Perales-Puchalt, A, Anadon, CM, Costich, TL, Harro, CM, Walrath, J, Ming, Q, Tcyganov, E, Buras, AL, Rigolizzo, KE, Mandal, G, Lajoie, J, Ophir, M, Tchou, J, Marchion, D, Luca, VC, Bobrowicz, P, McLaughlin, B, Eskiocak, U, Schmidt, M, Cubillos-Ruiz, JR, Rodriguez, PC, Gabrilovich, DI & Conejo-Garcia, JR 2020, 'BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells', Science, vol. 369, no. 6506, pp. 942-949. https://doi.org/10.1126/science.aay2767

TY - JOUR

T1 - BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells

AU - Payne, K. K.

AU - Mine, J. A.

AU - Biswas, S.

AU - Chaurio, R. A.

AU - Perales-Puchalt, A.

AU - Anadon, C. M.

AU - Costich, T. L.

AU - Harro, C. M.

AU - Walrath, J.

AU - Ming, Q.

AU - Tcyganov, E.

AU - Buras, A. L.

AU - Rigolizzo, K. E.

AU - Mandal, G.

AU - Lajoie, J.

AU - Ophir, M.

AU - Tchou, J.

AU - Marchion, D.

AU - Luca, V. C.

AU - Bobrowicz, P.

AU - McLaughlin, B.

AU - Eskiocak, U.

AU - Schmidt, M.

AU - Cubillos-Ruiz, J. R.

AU - Rodriguez, P. C.

AU - Gabrilovich, D. I.

AU - Conejo-Garcia, J. R.

N1 - 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 Buras, Andrea L Rigolizzo, Kristen E Mandal, Gunjan Lajoie, Jason Ophir, Michael Tchou, Julia Marchion, Douglas Luca, Vincent C Bobrowicz, Piotr McLaughlin, Brooke Eskiocak, Ugur Schmidt, Michael Cubillos-Ruiz, Juan R Rodriguez, Paulo C Gabrilovich, Dmitry I Conejo-Garcia, Jose R eng U01 CA232758/CA/NCI NIH HHS/ P30 CA010815/CA/NCI NIH HHS/ T32 CA009140/CA/NCI NIH HHS/ R01 CA211913/CA/NCI NIH HHS/ R01 CA240434/CA/NCI NIH HHS/ R01 CA157664/CA/NCI NIH HHS/ R01 NS114653/NS/NINDS NIH HHS/ R01 CA178687/CA/NCI NIH HHS/ P30 CA076292/CA/NCI NIH HHS/ R21 CA248106/CA/NCI NIH HHS/ R01 CA124515/CA/NCI NIH HHS/ R01 CA184185/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2020/08/21 Science. 2020 Aug 21;369(6506):942-949. doi: 10.1126/science.aay2767.

PY - 2020

Y1 - 2020

N2 - Gamma delta (gammadelta) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of gammadelta T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate alphabeta and gammadelta T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive alphabeta T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of alphabeta T cell effector activity and BTN2A1-dependent gammadelta lymphocyte cytotoxicity against BTN3A1(+) cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by alphabeta and gammadelta T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

AB - Gamma delta (gammadelta) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of gammadelta T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate alphabeta and gammadelta T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive alphabeta T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of alphabeta T cell effector activity and BTN2A1-dependent gammadelta lymphocyte cytotoxicity against BTN3A1(+) cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by alphabeta and gammadelta T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

KW - Animals Antibodies, Monoclonal/therapeutic use Antigens, CD/genetics/immunology Butyrophilins/antagonists & inhibitors/genetics/immunology Female Humans Immunotherapy/methods Intraepithelial Lymphocytes/immunology Mice Mice, Transgenic Ovarian Neoplasms/i

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U2 - 10.1126/science.aay2767

DO - 10.1126/science.aay2767

M3 - Article

SN - 1095-9203

VL - 369

SP - 942

EP - 949

JO - Science

JF - Science

IS - 6506

ER -

BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells

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BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells

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