FULL-LENGTH ARTICLEClinical ResearchIdentification of prognostic factors for γδT cell immunotherapy in patients with solid tumor
Introduction
γδT cells, which are innate-like T lymphocytes characterized by T cell receptors (TCRs) composed of γ and δ chains, are widely distributed in the peripheral blood and mucosal tissues [1]. It has been demonstrated that γδT cells rapidly recognize exogenous pathogens and endogenous stress-induced ligands in a major histocompatibility complex (MHC)-unrestricted manner and initiate adaptive immunity, acting as a first line of immune defense [2]. Activated γδT cells have been reported to exhibit multiple effector functions, including cytotoxicity against infected or tumor cells, cytokine and chemokine production, antigen-presenting functions, and regulatory abilities [3], thus allowing them to participate in the fight against an array of diseases, including infections, allergy, autoimmunity, and cancer [4], [5], [6], [7].
Regarding the antitumor function of γδT cells, it has been shown that γδT cells induce antibody-dependent cell-mediated cytotoxicity (ADCC) effects similar to natural killer (NK) cells, thus resulting in the lysis of tumor cells. In several other studies, γδT cells have also been shown to mediate ADCC effects on tumor cells via CD16 in the presence of therapeutic antitumor monoclonal antibodies [8,9]. Moreover, γδT cells have antitumor roles via their modulation of other effector cells. For example, Vγ9Vδ2 T cells, which are a major population of γδT cells, process endogenous antigens along the MHC-I peptide presentation pathway, which may promote antitumor adaptive immunity via the cross-presentation of tumor antigens [10]. Vγ9Vδ2 T cells activated by HMB-PP promote Th1 responses by inducing dendritic cell maturation and IL-12 secretion, which may facilitate antitumor immunity [11]. Isopentenyl pyrophosphate-expanded Vγ9Vδ2 T cells induce NK cells to recognize and kill tumor cells that are usually resistant to NK cytolysis by increasing NKG2D expression levels on their surface through CD137L co-stimulation [12]. Phosphoantigen-activated antigen presenting cells-like Vγ9Vδ2 T cells present glycolipid antigens to invariant NKT cells in a CD1d-restricted and α-GalCer-dependent manner and subsequently initiate antitumor responses [13]. Taken together, these results suggest that Vγ9Vδ2 T cells exert antitumor effects primarily by direct killing and ADCC-dependent cytolysis and by regulating the functions of other innate and adaptive immune cells.
Recently, in vitro γδT cell culture has been feasible in the presence of zoledronate and IL-2. Zoledronate is a type of bisphosphonate, a chelate of calcium ion, which inhibits farnesyl pyrophosphate synthetase. The osteolytic reaction of osteoclasts is suppressed when the production of farnesyl pyrophosphate is inhibited. By contrast, the level of isopentenyl pyrophosphate, which induces clonal expansion and activation of γδT cells, is increased in the presence of zoledronate [14]. Thus, the clinical-scale expansion of γδT cells along with Vγ9Vδ2 T cells via direct stimulation by phosphoantigens or the induction of agonist accumulation with aminobisphosphonates makes γδT cell-based cancer immunotherapy feasible [15]. Phase 1 and 2 clinical trials of this immunotherapy have been conducted in patients with various tumor types, and objective tumor responses have been observed [16,17].
However, the efficacy of γδT cell immunotherapy for a large number of patients with solid tumors remains unclear. Since 2007, we have treated 131 patients with various types of cancer using γδT cell immunotherapy combined with or without standard therapies such as chemotherapy, surgical operation, and radiation therapy. In this study, we retrospectively investigated the efficacy of γδT cell immunotherapy in the treatment of patients with advanced solid tumors and determined the prognostic factors for γδT cell immunotherapy. Furthermore, we examined lymphocyte profiles associated with antitumor immunoresponses before and after γδT cell immunotherapy in one third of patients enrolled in the study. Finally, we determined the prognostic factor that might be used to predict the response of patients with solid tumors to γδT cell immunotherapy.
Section snippets
Patients
This study was conducted from 1 April 2007 to 30 September 2017. One hundred thirty-one patients who were diagnosed as having malignant tumor on the basis of histopathological findings were enrolled and evaluated after six cycles of γδT cell immunotherapy with or without chemotherapy, surgical operation, and radiation therapy. The institutional review board of the hospital approved the study, and written informed consent was obtained from the patients. The clinical diagnoses of the enrolled
Patient characteristics
A total of 131 patients, comprising 64 males and 67 females with an average age of 61 years (range, 27–82 years), were studied (Table 1). Most of the patients had a performance status score of 0 or 1. Two thirds of the patients had undergone surgical operation or chemotherapy as a prior therapy. One third of the enrolled patients (39 patients) were evaluated by flow cytometry before and after γδT cell immunotherapy (see the FCM group Table 1; see supplementary Table 1). The background
Discussion
We conducted γδT cell immunotherapy on 131 patients with solid tumors and found that the therapy was safe and feasible for any type of malignant tumor. It has been reported that γδT cells are attractive candidates for antitumor cell-based immunotherapy because of their potent MHC-unrestricted antitumor effector activities [19]. Furthermore, it has been shown that pre-clinical and clinical studies paved the way for Vγ9Vδ2 T cell-mediated immunotherapy given the high frequency and broad antitumor
Funding
No funding was received.
Declaration of Competing Interests
The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
Author Contributions
Conception and design of the study: RT, TK, and SG. Administrative support: SO, EM, HI, and EO. Collection and assembly of data: SO, EM, HI, EO, KN, KY, KM, TM, EM, and KT. Data analysis and interpretation: RT, SO, TK, and SG. All authors have approved the final article.
Acknowledgments
The authors would like to express our special thanks to all participating patients and their families. They also thank Y. Yamashita, Medinet Co., Ltd., for support in data analysis.
Ethics approval and consent to participate
Each center's institutional review board or ethics committee approved the study. The trial followed the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research. All patients provided their written informed consent for both the study and this article.
Availability of data and material
All data are available via the corresponding author.
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