BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells

  • Science. 2020 Aug 21;369(6506):942-949. doi: 10.1126/science.aay2767.
Kyle K Payne  1 ,  Jessica A Mine  1 ,  Subir Biswas  1 ,  Ricardo A Chaurio  1 ,  Alfredo Perales-Puchalt  2 ,  Carmen M Anadon  1 ,  Tara Lee Costich  1 ,  Carly M Harro  1  3 ,  Jennifer Walrath  2 ,  Qianqian Ming  4 ,  Evgenii Tcyganov  2 ,  Andrea L Buras  5 ,  Kristen E Rigolizzo  1 ,  Gunjan Mandal  1 ,  Jason Lajoie  6 ,  Michael Ophir  6 ,  Julia Tchou  7 ,  Douglas Marchion  8 ,  Vincent C Luca  4 ,  Piotr Bobrowicz  6 ,  Brooke McLaughlin  6 ,  Ugur Eskiocak  6 ,  Michael Schmidt  6 ,  Juan R Cubillos-Ruiz  9 ,  Paulo C Rodriguez  1 ,  Dmitry I Gabrilovich  2 ,  Jose R Conejo-Garcia  10  5
Affiliations
  • 1. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 2. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 3. Department of Cell Biology, Microbiology, and Molecular Biology and Cancer Biology PhD Program, University of South Florida, Tampa, FL 33620, USA.
  • 4. Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 5. Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 6. Compass Therapeutics, Cambridge, MA 02142, USA.
  • 7. Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
  • 8. Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
  • 9. Department of Obstetrics and Gynecology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
  • 10. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. [email protected].
PMID: 32820120 DOI: 10.1126/science.aay2767
Abstract

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ 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 αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ Cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

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