National Academy of Agricultural Sciences (NAAS)
|
PRINT ISSN : 2319-7692
Online ISSN : 2319-7706 Issues : 12 per year Publisher : Excellent Publishers Email : editorijcmas@gmail.com / submit@ijcmas.com Editor-in-chief: Dr.M.Prakash Index Copernicus ICV 2018: 95.39 NAAS RATING 2020: 5.38 |
Bisphosphonates (BPs) are traditionally used to manage bone diseases, but recent evidence suggests they may play a significant role in cancer immunotherapy by modulating γδ T cell activity. These agents, particularly nitrogen-containing bisphosphonates, activate Vγ9Vδ2 T cells, enhancing their cytotoxicity against tumor cells. However, gaps remain in understanding the differential effects of bisphosphonates on various γδ T cell subsets, optimal dosing regimens, and their impact on the broader tumor microenvironment. This review synthesizes knowledge on bisphosphonate-induced γδ T cell modulation, explores potential resistance mechanisms, and evaluates clinical applicability across different tumor types. It identifies biomarkers for patient stratification, considers synergistic effects with other therapies, and discusses the economic and practical implications of integrating bisphosphonates into standard oncology practice. Addressing these gaps is essential for optimizing bisphosphonates as immunomodulatory agents, advancing cancer immunotherapy strategies, and improving patient outcomes.
Acosta-Ramirez E, Tram C, Kampen R M, Tillman M R, Schwendener R A, Xing Z, et al., Respiratory macrophages regulate CD4 T memory responses to mucosal immunization with recombinant adenovirus-based vaccines. CellImmunol. 2016 Dec;310:53-62. https://doi.org/10.1016/j.cellimm.2016.07.006.
Bulut O, Kilic G, Debisarun PA, Röring RJ, Sun S, Kolkman M, et al., Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination. ImmunolLett. 2024 Jun;267:106851. https://doi.org/10.1016/j.imlet.2024.106851.
Cao Y, Qiao B, Chen Q, Xie Z, Dou X, Xu L, et al., Tumor microenvironment remodeling via targeted depletion of M2-like tumor-associated macrophages for cancer immunotherapy. Acta Biomater. 2023 Apr 1;160:239-251. https://doi.org/10.1016/j.actbio.2023.02.006.
Cho S Y, Jeong S M, Jeon Y J, Yang S J, Hwang J E, Yoo BM, et al., WT1 pulsed human CD141+ dendritic cell vaccine has high potential in solid tumor-targeted immunotherapy. Int J Mol Sci. 2023 Jan 12;24(2):1501. https://doi.org/10.3390/ijms24021501.
Duault C, Franchini D M, Familliades J, Cayrol C, Roga S, Girard J P, et al., TCRVγ9 γδ T cell response to IL-33: a CD4 T cell-dependent mechanism. J Immunol. 2016 Jan 1;196(1):493-502. https://doi.org/10.4049/jimmunol.1500260.
Eiraku Y, Terunuma H, Yagi M, Deng X, Nicol A J, Nieda M. Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors. Clin ExpImmunol. 2018 Oct;194(1):54-66. https://doi.org/10.1111/cei.13185.
Fowler D W, Copier J, Dalgleish A G, Bodman-Smith M D. Zoledronic acid causes γδ T cells to target monocytes and down-modulate inflammatory homing. Immunology. 2014 Dec;143(4):539-49. https://doi.org/10.1111/imm.12331.
Girard P, Ponsard B, Charles J, Chaperot L, Aspord C. Potent bidirectional cross-talk between plasmacytoid dendritic cells and γδT cells through BTN3A, type I/II IFNs and immune checkpoints. Front Immunol. 2020 May 6;11:861. https://doi.org/10.3389/fimmu.2020.00861.
Hodgins N O, Al-Jamal W T, Wang J T, Klippstein R, Costa P M, Sosabowski J K, et al., Investigating in vitro and in vivo αvβ6 integrin receptor-targeting liposomal alendronate for combinatory γδ T cell immunotherapy. J Control Release. 2017 Jun 28;256:141-152. https://doi.org/10.1016/j.jconrel.2017.04.025.
Hodgins N O, Al-Jamal W T, Wang J T, Parente-Pereira A C, Liu M, Maher J, et al., In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice. J Control Release. 2016 Nov 10;241:229-241. https://doi.org/10.1016/j.jconrel.2016.09.023.
Hodgins N O, Wang J T, Al-Jamal K T. Nano-technology based carriers for nitrogen-containing bisphosphonates delivery as sensitisers of γδ T cells for anticancer immunotherapy. Adv Drug Deliv Rev. 2017 May 15;114:143-160. https://doi.org/10.1016/j.addr.2017.07.003 .
Hu L, Wen Y, Xu J, Wu T, Zhang C, Wang J, et al., Pretreatment with bisphosphonate enhances osteogenesis of bone marrow mesenchymal stem cells. StemCells Dev. 2017 Jan 15;26(2):123-132. https://doi.org/10.1089/scd.2016.0173.
Kar S, Colino J, Snapper C M. Distinct cellular pathways for induction of CD4+ T cell-dependent antibody responses to antigen expressed by intact bacteria versus isolated soluble antigen. J Immunol. 2016 May 15;196(10): 4204-13. https://doi.org/10.4049/jimmunol.1502550.
Kim M, Kim H, Han M, Hwang H J, Kim H, Im H J, et al., Characteristics of human peripheral blood γδ T cells expanded with zoledronate. Anticancer Res. 2021 Dec;41(12):6031-6038. https://doi.org/10.21873/anticanres.15422.
Koh KN, Im HJ, Kim H, Kim N, Choi ES, Park CJ, et al., αβ T-cell-depleted haploidentical hematopoietic cell transplantation and zoledronate/interleukin-2 therapy in children with relapsed, high-risk neuroblastoma. Bone Marrow Transplant. 2019 Feb;54(2):348-352. https://doi.org/10.1038/s41409-018-0305-3.
Kopecka J, Porto S, Lusa S, Gazzano E, Salzano G, Pinzòn-Daza ML, et al., Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors. Oncotarget. 2016 Apr 12;7(15):20753-72. https://doi.org/10.18632/oncotarget.8012.
Le Burel S, Thepenier C, Boutin L, Lataillade JJ, Peltzer J. Effect of mesenchymal stromal cells on T cells in a septic context: immunosuppression or immunostimulation? StemCells Dev. 2017 Oct 15;26(20):1477-1489. https://doi.org/10.1089/scd.2016.0184.
Lee YT, Kim KH, Hwang HS, Lee Y, Kwon YM, Ko EJ, et al., Innate and adaptive cellular phenotypes contributing to pulmonary disease in mice after respiratory syncytial virus immunization and infection. Virology. 2015 Nov;485:36-46. https://doi.org/10.1016/j.virol.2015.07.001.
Liu B, Yang Q, Cheng Y, Liu M, Ji Q, Zhang B, et al., Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression. Acta Biomater. 2023 Aug;166:640-654. https://doi.org/10.1016/j.actbio.2023.05.038.
Man F, Lim L, Volpe A, Gabizon A, Shmeeda H, Draper B, et al., In vivo PET tracking of 89Zr-labeled Vγ9Vδ2 T cells to mouse xenograft breast tumors activated with liposomal alendronate. Mol Ther. 2019 Jan 2;27(1):219-229. https://doi.org/10.1016/j.ymthe.2018.10.006.
Merli P, Algeri M, Galaverna F, Milano GM, Bertaina V, Biagini S, et al., Immune modulation properties of zoledronic acid on TcRγδ T-lymphocytes after TcRαβ/CD19-depleted haploidentical stem cell transplantation: an analysis on 46 pediatric patients affected by acute leukemia. Front Immunol. 2020 May 12;11:699. https://doi.org/10.3389/fimmu.2020.00699.
Mizuta S, Tagod MSO, Iwasaki M, Nakamura Y, Senju H, Mukae H, et al., Synthesis and immunomodulatory activity of fluorine-containing bisphosphonates. ChemMedChem. 2019 Feb 19;14(4):462-468. https://doi.org/10.1002/cmdc.201800764.
Murday AS, Chaudhry S, Pauza CD. Interleukin-18 activates Vγ9Vδ2+ T cells from HIV-positive individuals: recovering the response to phosphoantigen. Immunology. 2017 Aug;151(4):385-394. https://doi.org/10.1111/imm.12735.
Nguyen TT, Nguyen BT, Tran KV, Tran CK, Trinh HL, Hoang HH, et al., Experience of autologous immunotherapy for non-small cell lung cancer using zoledronate-activated gammadelta T cells. Clin Lab. 2024 Jan 1;70(1). https://doi.org/10.7754/Clin.Lab.2023.230663.
Nie M, Wu S, Chen Y, Wu Y, Chen R, Liu Y, et al., Micronanoparticled risedronate exhibits potent vaccine adjuvant effects. J Control Release. 2024 Jan;365:369-383. https://doi.org/10.1016/j.jconrel.2023.11.025.
Nieda M, Terunuma H, Eiraku Y, Deng X, Nicol AJ. Effective induction of melanoma-antigen-specific CD8+ T cells via Vγ9γδT cell expansion by CD56(high+) interferon-α-induced dendritic cells. Exp Dermatol. 2015 Jan;24(1):35-41. https://doi.org/10.1111/exd.12581.
Okuno D, Sugiura Y, Sakamoto N, Tagod MSO, Iwasaki M, Noda S, et al., Comparison of a novel bisphosphonate prodrug and zoledronic acid in the induction of cytotoxicity in human Vγ2Vδ2 T cells. Front Immunol. 2020 Jul 21;11:1405. https://doi.org/10.3389/fimmu.2020.01405.
Osada T, Nagaoka K, Takahara M, Yang XY, Liu CX, Guo H, et al., Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors. J Immunother. 2015 May;38(4):155-64. https://doi.org/10.1097/CJI.0000000000000075.
Parente-Pereira AC, Shmeeda H, Whilding LM, Zambirinis CP, Foster J, van der Stegen SJ, et al., Adoptive immunotherapy of epithelial ovarian cancer with Vγ9Vδ2 T cells, potentiated by liposomal alendronic acid. J Immunol. 2014 Dec 1;193(11):5557-66. https://doi.org/10.4049/jimmunol.1402200.
Patra S, Ghosal S, Shand H, Mondal R, Rath A, Kumar Jana S, et al., Function of gamma delta (γδ) T cell in cancer with special emphasis on cervical cancer. Hum Immunol. 2023 Dec;84(12):110724. https://doi.org/10.1016/j.humimm.2023.110724.
Poonia B. Adoptive transfer of aminobisphonate-expanded Vγ9Vδ2+ T cells does not control HIV replication in a humanized mouse model. Immunotherapy. 2016 May;8(5):521-6. https://doi.org/10.2217/imt-2015-0003.
Sun B, Zhao X, Wu Y, Cao P, Movahedi F, Liu J, et al., Mannose-functionalized biodegradable nanoparticles efficiently deliver DNA vaccine and promote anti-tumor immunity. ACS ApplMater Interfaces. 2021 Mar 31;13(12):14015-14027. https://doi.org/10.1021/acsami.1c01401.
Tanaka Y, Iwasaki M, Murata-Hirai K, Matsumoto K, Hayashi K, Okamura H, et al., Anti-tumor activity and immunotherapeutic potential of a bisphosphonate prodrug. Sci Rep. 2017 Jul 20;7(1):5987. https://doi.org/10.1038/s41598-017-05553-0.
Tanaka Y, Murata-Hirai K, Iwasaki M, Matsumoto K, Hayashi K, Kumagai A, et al., Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug. Cancer Sci. 2018 Mar;109(3):587-599. https://doi.org/10.1111/cas.13491.
Wang L, Li Z, Ciric B, Safavi F, Zhang GX, Rostami A. Selective depletion of CD11c+ CD11b+ dendritic cells partially abrogates tolerogenic effects of intravenous MOG in murine EAE. Eur J Immunol. 2016 Oct;46(10):2454-2466. https://doi.org/10.1002/eji.201546274.
Wang S, Li H, Ye C, Lin P, Li B, Zhang W, et al., Valproic acid combined with zoledronate enhance γδ T cell-mediated cytotoxicity against osteosarcoma cells via the accumulation of mevalonate pathway intermediates. Front Immunol. 2018 Feb 27;9:377. https://doi.org/10.3389/fimmu.2018.00377.
Wang Y, Wang L, Seo N, Okumura S, Hayashi T, Akahori Y, et al., CAR-modified Vγ9Vδ2 T cells propagated using a novel bisphosphonate prodrug for allogeneic adoptive immunotherapy. Int J Mol Sci. 2023 Jun 29;24(13):10873. https://doi.org/10.3390/ijms241310873.
Yamaguchi Y, Katata Y, Okawaki M, Sawaki A, Yamamura M. A prospective observational study of adoptive immunotherapy for cancer using zoledronate-activated killer (ZAK) cells - an analysis for patients with incurable pancreatic cancer. Anticancer Res. 2022 Feb;42(2):1181-1187. https://doi.org/10.21873/anticanres.15584.
Yamaguchi Y, Katata Y, Okawaki M, Sawaki A, Yamamura M. A prospective observational study of adoptive immunotherapy for cancer using zoledronate-activated killer (ZAK) cells - an analysis for patients with incurable pancreatic cancer. Anticancer Res. 2016 May;36(5):2307-13. Retraction in: Anticancer Res. 2021 Aug;41(8):4181. https://doi.org/10.21873/anticanres.41.8.4181.
Zang X, Zhang X, Hu H, Qiao M, Zhao X, Deng Y, et al., Targeted delivery of zoledronate to tumor-associated macrophages for cancer immunotherapy. Mol Pharm. 2019 May 6;16(5):2249-2258. https://doi.org/10.1021/acs.molpharmaceut.9b00261.
Zhang X, Wei M, Zhang Z, Zeng Y, Zou F, Zhang S, et al., Risedronate-functionalized manganese-hydroxyapatite amorphous particles: a potent adjuvant for subunit vaccines and cancer immunotherapy. J Control Release. 2024 Mar;367:13-26. https://doi.org/10.1016/j.jconrel.2024.01.033.
Zheng Y, Wang PP, Fu Y, Chen YY, Ding ZY. Zoledronic acid enhances the efficacy of immunotherapy in non-small cell lung cancer. IntImmunopharmacol. 2022 Sep;110:109030. https://doi.org/10.1016/j.intimp.2022.109030
Citations |
 |
 |
 |
 |
