Toll-like receptors(TLRs)are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses.TLR ligands represent a promising class of immunotherapeutics or va...Toll-like receptors(TLRs)are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses.TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response.The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer(NK)cells.However,the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear,and different TLR7/8 agonists have been found to induce different responses.In this study,we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes,stimulate the activation of splenic T,NK and natural killer T(NKT)cells,increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines,and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells(DCs).In a murine model,both agonists improved the antitumor effects of tumor lysate-loaded DCs,resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis.Further,we found that gardiquimod demonstrated more potent antitumor activity than imiquimod.These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy.More importantly,they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.展开更多
Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor metastasis.To overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that e...Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor metastasis.To overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic photoimmunotherapy.The AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor accumulation.AIRL could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs maturation.The synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant tumors.Simultaneously,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.展开更多
基金supported by grants from the Natural Science Foundation of China(no.90713033)the National 973 Basic Research Program of China(no.2007CB815800)the National 115 Key Project for HBV Research(no.2008ZX10002-008).
文摘Toll-like receptors(TLRs)are a family of highly conserved germline-encoded pattern-recognition receptors that are essential for host immune responses.TLR ligands represent a promising class of immunotherapeutics or vaccine adjuvants with the potential to generate an effective antitumor immune response.The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer(NK)cells.However,the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear,and different TLR7/8 agonists have been found to induce different responses.In this study,we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes,stimulate the activation of splenic T,NK and natural killer T(NKT)cells,increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines,and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells(DCs).In a murine model,both agonists improved the antitumor effects of tumor lysate-loaded DCs,resulting in delayed growth of subcutaneous B16 melanoma tumors and suppression of pulmonary metastasis.Further,we found that gardiquimod demonstrated more potent antitumor activity than imiquimod.These results suggest that TLR7/8 agonists may serve as potent innate and adaptive immune response modifiers in tumor therapy.More importantly,they can be used as vaccine adjuvants to potentiate the efficiency of DC-based tumor immunotherapy.
基金financially supported by National Natural Science Foundation of China(Nos.82172090,82302390 and 82072059)CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-058 and 2022-I2M-1-023)+3 种基金China Postdoctoral Science Foundation(No.2022M720502)Tianjin Municipal Natural Science Foundation(No.22JCQNJC00070)CAMS Union Young Scholars Support Program(No.2022051)Fundamental Research Funds for the Central Universities(No.2019PT320028)。
文摘Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor metastasis.To overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic photoimmunotherapy.The AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor accumulation.AIRL could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs maturation.The synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant tumors.Simultaneously,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.
