Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. R...Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistancein cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsicmechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulatetumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects toenhance the ICB response for therapeutic gain in cancer patients.展开更多
Transforming growth factor-β(TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of a...Transforming growth factor-β(TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis.Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases,including cancer,immune dysfunction,and fbrosis.In this review,we focus on TGFβ,a well-characterized family member that has a dichotomous role in cancer progression,acting in early stages as a tumor suppressor and in late stages as a tumor promoter.The functions of TGFβ are not limited to the regulation of proliferation,differentiation,apoptosis,epithelial-mesenchymal transition,and metastasis of cancer cells.Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition,promotion of angiogenesis,and suppression of the ant-tumor immune reaction.The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients.However,the critical function of TGFβin maintaining tissue homeostasis makes targeting TGFβa challenge.Here,we review the pleiotropic functions of TGFβin cancer initiation and progression,summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment,and discuss the remaining challenges and opportunities related to targeting this pathway.We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy,targeted therapy,radiotherapy,or immunotherapy.展开更多
基金a ZonMW grant(09120012010061)the Cancer Genomics Center Netherlands(CGC.NL.).
文摘Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistancein cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsicmechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulatetumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects toenhance the ICB response for therapeutic gain in cancer patients.
基金We apologize to authors whose papers could not be cited due to space limitations.We are grateful to Dieuwke Marvin and Adilson Fonseca Teixeira for a critical reading and comments.We thank Gerard van der Zon for the immunofluorescent staining images of NMuMG cells.Research on targeting TGFβ for cancer therapy in our laboratory is supported by the Cancer Genomics Centre Netherlands。
文摘Transforming growth factor-β(TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis.Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases,including cancer,immune dysfunction,and fbrosis.In this review,we focus on TGFβ,a well-characterized family member that has a dichotomous role in cancer progression,acting in early stages as a tumor suppressor and in late stages as a tumor promoter.The functions of TGFβ are not limited to the regulation of proliferation,differentiation,apoptosis,epithelial-mesenchymal transition,and metastasis of cancer cells.Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition,promotion of angiogenesis,and suppression of the ant-tumor immune reaction.The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients.However,the critical function of TGFβin maintaining tissue homeostasis makes targeting TGFβa challenge.Here,we review the pleiotropic functions of TGFβin cancer initiation and progression,summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment,and discuss the remaining challenges and opportunities related to targeting this pathway.We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy,targeted therapy,radiotherapy,or immunotherapy.
