Therapeutic Effects of ADU-S100 as STING Agonist and CpG ODN1826 as TLR9 Agonist in CT-26 Model of Colon Carcinoma

Iranian Journal of Veterinary Science and Technology

مقاله 4، دوره 15، شماره 2 - شماره پیاپی 31، مهر 2023، صفحه 29-37   

نوع مقاله: Research Articles

شناسه دیجیتال (DOI): 10.22067/ijvst.2023.80505.1223

نویسندگان

Sare Hajiabadi¹؛ Soodeh Alidadi¹؛ Mohammad Mehdi Ghahramani Senoo²؛ Zohreh Montakhab Farahi¹؛ Hamid Reza Farzin³؛ Alireza Haghparast^{* 1}

¹Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran .

²Program for Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

³Razi Vaccine and Serum Research Institute, Agriculture Research, Education and Extension Organization (AREEO), Mashhad, Iran.

چکیده

Cancer immunotherapy emerged as a novel therapeutic approach to destroy tumor cells, and it has grown toward clinical transition following successful fundamental research and clinical trials. Immunotherapy by efficacious adjuvants is critical for increasing protective immune responses against infectious diseases and cancers. STING and TLR9 agonists are interesting candidates for novel immunotherapies of cancers. In this study, the antitumoral effects of ADU-S100, as a potent STING agonist, and CpG ODN1826, as a TLR9 agonist, in single and combined forms in CT-26 colon adenocarcinoma model were evaluated. This model was induced in female BALB/c mice which were divided into five groups treated with PBS, ADU-S100 (20 and 40 µg), CpG ODN (40 µg), and ADU-S100 (20 µg)+CpG ODN (20 µg). The tumor volumes and weights of mice were measured every other day. On the 30th day, the tumor, spleen, and liver tissues of mice were isolated for histopathological assessment. Hematological analysis was performed on heart blood. Intratumoral injection of agonists induced significant tumor suppression in all treatment groups with profound effect in the combination group that received half concentration of single form. Moreover, the histopathological analysis of tumor tissues showed the presence of apoptotic and inflammatory cells and increased the number of lymphocytes in the blood samples of the treatment groups indicating the effective role of these agonists in clearing the tumor. Therefore, a such synergy of adjuvants may have an effective role in cancer immunotherapy and offer new perspectives on the combination of agonists that trigger innate immune sensors during malignancy.

کلیدواژه‌ها

STING agonist؛ TLR9 agonist؛ Synergistic effect؛ Immunotherapy؛ Colon carcinoma model

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مراجع

1.    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-9. Doi:10.1056/NEJMoa1411087.
2.    Fay EK, Graff JN. Immunotherapy in Prostate Cancer. Cancers. 2020;12(7):1752. Doi: 10.3390/cancers12071752.
3.    Banstola A, Jeong J-H, Yook S. Immunoadjuvants for cancer immunotherapy: A review of recent developments. Acta Biomaterialia. 2020; 114:16-30. Doi: 10.1016/j.actbio.2020.07.063
4.    Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov. 2006;5(6):471-84. Doi: 10.1038/nrd2059.
5.    Yu C, An M, Li M, Liu H. Immunostimulatory Properties of Lipid Modified CpG Oligonucleotides. Mol Pharm. 2017;14(8):2815-23. Doi:10.1021/acs.molpharmaceut.7b00335.
6.    Krieg AM. Development of TLR9 agonists for cancer therapy. J Clin Invest. 2007;117(5):1184-94. Doi: 10.1172/JCI31414.
7.    Sierra H, Cordova M, Chen CJ, Rajadhyaksha M. Confocal imaging-guided laser ablation of basal cell carcinomas: an ex vivo study. J Invest Dermatol. 2015;135(2):612-5. Doi: 10.1038/jid.2014.371.
8.    Krieg AM. Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene. 2008;27(2):161-7. Doi: 10.1038/sj.onc.1210911.
9.    Corrales L, Gajewski TF. Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer. Clin Cancer Res. 2015;21(21):4774-9. Doi: 10.1158/1078-0432.CCR-15-1362.
10.    Levy ES, Chang R, Zamecnik CR, Dhariwala MO, Fong L, Desai TA. Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity. Mol Pharm. 2021;18(3):1014-25. Doi: 10.1021/acs.molpharmaceut.0c00984.
11.    Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep. 2015;11(7):1018-30. Doi: 10.1016/j.celrep.2015.04.031.
12.    Sallets A, Robinson S, Kardosh A, Levy R. Enhancing immunotherapy of STING agonist for lymphoma in preclinical models. Blood Adv. 2018;2(17):2230-41. Doi: 10.1182/bloodadvances.2018020040.
13.    Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, et al. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res. 2014;2(12):1199-208. Doi: 10.1158/2326-6066.CIR-14-0099.
14.    Corrales L, Gajewski TF. Endogenous and pharmacologic targeting of the STING pathway in cancer immunotherapy. Cytokine. 2016; 77: 245-7. Doi: 10.1016/j.cyto.2015.08.258.
15.    Bai G, Yu H, Guan X, Zeng F, Liu X, Chen B, et al. CpG immunostimulatory oligodeoxynucleotide 1826 as a novel nasal ODN adjuvant enhanced the protective efficacy of the periodontitis gene vaccine in a periodontitis model in SD rats. BMC Oral Health. 2021;21(1):403. Doi: 10.1186/s12903-021-01763-1.
16.    Corrales L, McWhirter SM, Dubensky TW, Jr., Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-11. Doi: 10.1172/JCI86892.
17.    Savitsky D, Tamura T, Yanai H, Taniguchi T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother. 2010;59(4):489-510. Doi: 10.1007/s00262-009-0804-6.
18.    Mocellin S, Nitti D. Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines. Med Res Rev. 2008;28(3):413-44. Doi: 10.1002/med.20110.
19.    Woo SR, Corrales L, Gajewski TF. Innate immune recognition of cancer. Annu Rev Immunol. 2015; 33: 445-74. Doi: 10.1146/annurev-immunol-032414-112043.
20.    Li T, Cheng H, Yuan H, Xu Q, Shu C, Zhang Y, et al. Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. Sci Rep. 2016; 6: 19049. Doi: 10.1038/srep19049.
21.    Demaria O, De Gassart A, Coso S, Gestermann N, Di Domizio J, Flatz L, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408-13. Doi: 10.1073/pnas.1512832112.
22.    Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother. 2015;64(8):1057-66. Doi: 10.1007/s00262-015-1713-5.
23.    Tang CH, Zundell JA, Ranatunga S, Lin C, Nefedova Y, Del Valle JR, et al. Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells. Cancer Res. 2016;76(8):2137-52. Doi: 10.1158/0008-5472.CAN-15-1885.
24.    Huang L, Ge X, Liu Y, Li H, Zhang Z. The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy. Pharmaceutics. 2022;14(6). Doi: 10.3390/pharmaceutics14061228.
25.    Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014;41(5):843-52. Doi: 10.1016/j.immuni.2014.10.019.
26.    Temizoz B, Kuroda E, Ohata K, Jounai N, Ozasa K, Kobiyama K, et al. TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN. Eur J Immunol. 2015;45(4):1159-69. Doi: 10.1002/eji.201445132.
27.    Temizoz B, Hioki K, Kobari S, Jounai N, Kusakabe T, Lee MSJ, et al. Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation. Int Immunol. 2022;34(7):353-64. Doi: 10.1093/intimm/dxac012.
28.    Cai L, Du X, Zhang C, Yu S, Liu L, Zhao J, et al. Robust immune response stimulated by in situ injection of CpG/αOX40/cGAMP in αPD-1-resistant malignancy. Cancer Immunol Immunother. 2022;71(7):1597-609. Doi: 10.1007/s00262-021-03095-z.
29.    Dorostkar F, Arashkia A, Roohvand F, Shoja Z, Navari M, Mashhadi Abolghasem Shirazi M, et al. Co-administration of 2'3'-cGAMP STING activator and CpG-C adjuvants with a mutated form of HPV 16 E7 protein leads to tumor growth inhibition in the mouse model. Infect Agent Cancer. 2021;16(1):7. Doi: 10.1186/s13027-021-00346-7.
30.    Kitayama J, Yasuda K, Kawai K, Sunami E, Nagawa H. Circulating lymphocyte is an important determinant of the effectiveness of preoperative radiotherapy in advanced rectal cancer. BMC Cancer. 2011;11: 64. Doi: 10.1186/1471-2407-11-64.
31.    Seth A, Lee H, Cho MY, Park C, Korm S, Lee JY, et al. Combining vasculature disrupting agent and Toll-like receptor 7/8 agonist for cancer therapy. Oncotarget. 2017;8(3):5371-81. Doi: 10.18632/oncotarget.14260.
32.    Luo M, Liu Z, Zhang X, Han C, Samandi LZ, Dong C, et al. Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy. J Control Release. 2019; 300: 154-60. Doi: 10.1016/j.jconrel.2019.02.036.