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1.
Eur J Pharmacol ; 967: 176383, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38311281

ABSTRACT

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells. Herein, we identified a novel selective TLR7 agonist, GY101, and determined its ability to activate TLR7. In summary, in vitro, compound GY101 significantly induced the secretion of IL-6, IL-12, TNF-α and IFN-γ in mouse splenic lymphocytes; in vivo, peritumoral injection of GY101 significantly suppressed colon cancer CT26, as well as poorly immunogenic B16-F10 and 4T1 cancer cell-derived tumor growth by activating the infiltration of lymphocytes and polarization of M2-like macrophages into M1-like macrophages. These results demonstrate that GY101, as a potent TLR7 agonist, holds great potential for cancer immunotherapy.


Subject(s)
Colonic Neoplasms , Toll-Like Receptor 7 , Animals , Mice , Toll-Like Receptor 7/agonists , Tumor Necrosis Factor-alpha , Interleukin-6 , Interleukin-12 , Adjuvants, Immunologic , Colonic Neoplasms/drug therapy
2.
Int J Mol Sci ; 25(1)2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38203835

ABSTRACT

JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8+ T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.


Subject(s)
Adenine , Bromodomain Containing Proteins , Melanoma , Succinates , Toll-Like Receptor 7 , Animals , Mice , Adenine/analogs & derivatives , Adjuvants, Immunologic , B7-H1 Antigen , CD8-Positive T-Lymphocytes , Nuclear Proteins , Toll-Like Receptor 7/agonists , Transcription Factors , Bromodomain Containing Proteins/antagonists & inhibitors
3.
World J Gastroenterol ; 21(26): 8052-60, 2015 Jul 14.
Article in English | MEDLINE | ID: mdl-26185376

ABSTRACT

AIM: To investigate the effects of our tumor vaccines on reversing immune tolerance and generating therapeutic response. METHODS: Vaccines were synthesized by solid phase using an Fmoc strategy, where a small molecule toll-like receptor-7 agonist (T7) was conjugated to a monoclonal gastric cancer 7 antigen mono-epitope (T7-MG1) or tri-epitope (T7-MG3). Cytokines were measured in both mouse bone marrow dendritic cells and mouse spleen lymphocytes after exposed to the vaccines. BALB/c mice were intraperitoneally immunized with the vaccines every 2 wk for a total of three times, and then subcutaneously challenged with Ehrlich ascites carcinoma (EAC) cells. Three weeks later, the mice were killed, and the tumors were surgically removed and weighed. Serum samples were collected from the mice, and antibody titers were determined by ELISA using an alkaline phosphate-conjugated detection antibody for total IgG. Antibody-dependent cell-mediated cytotoxicity was detected by the lactate dehydrogenase method using natural killer cells as effectors and antibody-labeled EAC cells as targets. Cytotoxic T lymphocyte activities were also detected by the lactate dehydrogenase method using lymphocytes as effectors and EAC cells as targets. RESULTS: Vaccines were successfully synthesized and validated by analytical high performance liquid chromatography and electrospray mass spectrometry, including T7, T7-MG1, and T7-MG3. Rapid inductions of tumor necrosis factor-α and interleukin-12 in bone marrow dendritic cells and interferon γ and interleukin-12 in lymphocytes occurred in vitro after T7, T7-MG1, and T7-MG3 treatment. Immunization with T7-MG3 reduced the EAC tumor burden in BALB/c mice to 62.64% ± 5.55% compared with PBS control (P < 0.01). Six or nine weeks after the first immunization, the monoclonal gastric cancer 7 antigen antibody increased significantly in the T7-MG3 group compared with the PBS control (P < 0.01). As for antibody-dependent cell-mediated cytotoxicity, antisera obtained by immunization with T7-MG3 were able to markedly enhance cell lysis compared to PBS control (31.58% ± 2.94% vs 18.02% ± 2.26%; P < 0.01). As for cytotoxic T lymphocytes, T7-MG3 exhibited obviously greater cytotoxicity compared with PBS control (40.92% ± 4.38% vs 16.29% ± 1.90%; P < 0.01). CONCLUSION: A successful method is confirmed for the design of gastric cancer vaccines by chemical conjugation of T7 and multi-repeat-epitope of monoclonal gastric cancer 7 antigen.


Subject(s)
Antigens, Neoplasm/immunology , Cancer Vaccines/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , Immunoconjugates/pharmacology , Membrane Glycoproteins/agonists , Toll-Like Receptor 7/agonists , Tumor Escape/drug effects , Animals , Antibody-Dependent Cell Cytotoxicity , Cancer Vaccines/administration & dosage , Cancer Vaccines/chemical synthesis , Cancer Vaccines/immunology , Carcinoma, Ehrlich Tumor/immunology , Carcinoma, Ehrlich Tumor/pathology , Cells, Cultured , Cytokines/metabolism , Epitopes , Female , Immunization Schedule , Immunoconjugates/administration & dosage , Injections, Intraperitoneal , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Mice, Inbred BALB C , Signal Transduction/drug effects , Superantigens , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Time Factors , Toll-Like Receptor 7/immunology , Toll-Like Receptor 7/metabolism , Tumor Burden
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