Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive c...Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups.The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment(TME)into one with strong immunosuppression,facilitating the immune escape of HCC cells.Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes(e.g.,proteins and nucleic acids)for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming,ultimately creating a tumor-friendly microenvironment.Characterized by several intrinsic attributes,such as good stability(bilayer-like structure)and high biocompatibility(cell secretion),exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs,thus effectively triggering the HCC cell elimination by the immune system.This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.展开更多
Estrogen is involved in promoting lung cancer cell division and metastasis. MICA and MICB function as ligands for NKG2D, an important immunoreceptor expressed on natural killer （NK） cells. However, whether estrogen ...Estrogen is involved in promoting lung cancer cell division and metastasis. MICA and MICB function as ligands for NKG2D, an important immunoreceptor expressed on natural killer （NK） cells. However, whether estrogen regulates MICA/ B expression and affects tumor immune escape remains unknown. In this study, we measured the mRNA levels of MICA, MICB and ADAM 17in non-small cell lung cancer （NSCLC） cell lines treated with estrogen. Surface expression of MICA/B on LTEP-a2 and A549 was detected using flow cytometry. We demonstrate that both mRNA and secretory protein levels of M ICA/B in lung adenocarcinoma cell lines were upregulated by estradiol. Estradiol enhanced the expression of ADAM 17, which was associated with the secretion of MICA/B. This secretion of MICA/B downregulated the NKG2D receptor on the surface of NK92 cells and impaired the cytotoxic activity of NK cells. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. Furthermore, a significant correlation between the concentration of estradiol and the expression of MICA was found in tumor tissues of NSCLC patients. Therefore, we conclude that estrogen can regulate the expression and secretion of MICA/B through ADAM 17, which helps lung cancer cells escape NKG2D-mediated immune surveillance.展开更多
Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the can...Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.展开更多
Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor ...Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.展开更多
基金This work was supported in part by the National Natural Science Foundation of China(No.81871949 and 82171834 to H.Zhu)Jiangsu Six Talent Peaks Project(WSN-102 to H.Zhu)+1 种基金Dawn Project Foundation of Shanghai(No.21SG36 to T.Yang)Adjunct Talent Fund of Zhejiang Provincial People's Hospital(No.2021-YT to T.Yang).
文摘Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups.The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment(TME)into one with strong immunosuppression,facilitating the immune escape of HCC cells.Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes(e.g.,proteins and nucleic acids)for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming,ultimately creating a tumor-friendly microenvironment.Characterized by several intrinsic attributes,such as good stability(bilayer-like structure)and high biocompatibility(cell secretion),exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs,thus effectively triggering the HCC cell elimination by the immune system.This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.
基金This work was supported by the National Natural Science Foundation of China （81101552 and 81201598）, and the Natural Science Foundation of liangsu Province （BK2011571）.
文摘Estrogen is involved in promoting lung cancer cell division and metastasis. MICA and MICB function as ligands for NKG2D, an important immunoreceptor expressed on natural killer （NK） cells. However, whether estrogen regulates MICA/ B expression and affects tumor immune escape remains unknown. In this study, we measured the mRNA levels of MICA, MICB and ADAM 17in non-small cell lung cancer （NSCLC） cell lines treated with estrogen. Surface expression of MICA/B on LTEP-a2 and A549 was detected using flow cytometry. We demonstrate that both mRNA and secretory protein levels of M ICA/B in lung adenocarcinoma cell lines were upregulated by estradiol. Estradiol enhanced the expression of ADAM 17, which was associated with the secretion of MICA/B. This secretion of MICA/B downregulated the NKG2D receptor on the surface of NK92 cells and impaired the cytotoxic activity of NK cells. Estradiol enhanced the expression of ADAM17, which was associated with the secretion of MICA/B. Furthermore, a significant correlation between the concentration of estradiol and the expression of MICA was found in tumor tissues of NSCLC patients. Therefore, we conclude that estrogen can regulate the expression and secretion of MICA/B through ADAM 17, which helps lung cancer cells escape NKG2D-mediated immune surveillance.
基金supported by the National Natural Science Foundation of China(No.81930102 to Bo Yang),the National Natural Science Foundation of China(No.82273949 to Ling Ding),the National Natural Science Foundation of China(No.82104196 to Xi Chen)。
文摘Lipids have been found to modulate tumor biology,including proliferation,survival,and metastasis.With the new understanding of tumor immune escape that has developed in recent years,the influence of lipids on the cancer—immunity cycle has also been gradually discovered.First,regarding antigen presentation,cholesterol prevents tumor antigens from being identified by antigen presenting cells.Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells,impairing antigen presentation to T cells.Prostaglandin E2(PGE2)reduce the accumulation of tumor-infiltrating dendritic cells.Regarding T-cell priming and activation,cholesterol destroys the structure of the T-cell receptor and reduces immunodetection.In contrast,cholesterol also promotes T-cell receptor clustering and relative signal transduction.PGE2 represses T-cell proliferation.Finally,regarding T-cell killing of cancer cells,PGE2 and cholesterol weaken granule-dependent cytotoxicity.Moreover,fatty acids,cholesterol,and PGE2 can improve the activity of immunosuppressive cells,increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines.Given the regulatory role of lipids in the cancer—immunity cycle,drugs that modulate fatty acids,cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy.These strategies have been studied in both preclinical and clinical studies.
文摘Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.
