title: Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity.
abstract: Amino-bis-phosphonates (N-BPs) such as zoledronate (Zol) have been used in anticancer clinical trials due to their ability to upregulate pyrophosphate accumulation promoting antitumor Vγ9Vδ2 T cells. The butyrophilin 3A (BTN3A, CD277) family, mainly the BTN3A1 isoform, has emerged as an important structure contributing to Vγ9Vδ2 T cells stimulation. It has been demonstrated that the B30.2 domain of BTN3A1 can bind phosphoantigens (PAg) and drive the activation of Vγ9Vδ2 T cells through conformational changes of the extracellular domains. Moreover, BTN3A1 binding to the cytoskeleton, and its consequent membrane stabilization, is crucial to stimulate the PAg-induced tumor cell reactivity by human Vγ9Vδ2 T cells. Aim of this study was to investigate the relevance of BTN3A1 in N-BPs-induced antitumor response in colorectal cancer (CRC) and the cell types involved in the tumor microenvironment. In this paper, we show that (i) CRC, exposed to Zol, stimulates the expansion of Vδ2 T lymphocytes with effector memory phenotype and antitumor cytotoxic activity, besides sensitizing cancer cells to γδ T cell-mediated cytotoxicity; (ii) this effect is partially related to BTN3A1 expression and in particular with its cellular re-distribution in the membrane and cytoskeleton-associated fraction; (iii) BTN3A1 is detected in CRC at the tumor site, both on epithelial cells and on tumor-associated fibroblasts (TAF), close to areas infiltrated by Vδ2 T lymphocytes; (iv) Zol is effective in stimulating antitumor effector Vδ2 T cells fromex-vivoCRC cell suspensions; and (v) both CRC cells and TAF can be primed by Zol to trigger Vδ2 T cells.
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute , Milan, Italy.
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.affiliation: Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Delfina
authors.initials: D
authors.lastname: Costa
authors.affiliation: Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Roberta
authors.identifier: 0000-0002-2522-3716
authors.initials: R
authors.lastname: Venè
authors.affiliation: Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tosetti
authors.affiliation: Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ferrari
authors.affiliation: UOC Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini , Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Minghelli
authors.affiliation: Immunology Unit, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Roberto
authors.identifier: 0000-0002-9769-0954
authors.initials: R
authors.lastname: Benelli
authors.affiliation: Oncological Surgery, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Scabini
authors.affiliation: Oncological Surgery, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Romairone
authors.affiliation: Clinical Hematology, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Catellani
authors.affiliation: Biopolymers and Proteomics Unit IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Profumo
authors.affiliation: Molecular Oncology and Angiogenesis, IRCCS AOU San Martino-IST , Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
keywords: Amino-bis-phosphonates; butyrophilin; colorectal cancer; immunostimulation; phosphate antigens