Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selec...Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies.Inflammation-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains elusive.We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo.Higher A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer prognosis.Gain-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in mitochondria.Mechanistically,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein.Our findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.展开更多
基金National Natural Science Foundation of China(U21A20421)National Natural Science Foundation of China(82073882)+3 种基金National Natural Science Foundation of China(82203649)Guangdong Basic and Applied Basic Research Foundation(2020B1515120032)China Postdoctoral Science Foundation(2021M693648)Guangdong Esophageal Cancer Institute Science and Technology Program(M202001).
文摘Immune checkpoint inhibitors(ICIs)have induced durable clinical responses in a subset of patients with colorectal cancer(CRC).However,the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies.Inflammation-related molecule A20 is closely related to cancer immune response,but the effect of A20 on“eat-me”signal and immunotherapy efficacy remains elusive.We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo.Higher A20 expression was associated with less infiltration of immune cells including CD3(+),CD8(+)T cells and macrophages in CRC tissues and also poorer prognosis.Gain-and loss-A20 functional studies proved that A20 could decrease the“eat-me”signal calreticulin(CRT)protein on cell membrane translocation via upregulating stanniocalcin 1(STC1),binding to CRT and detaining in mitochondria.Mechanistically,A20 inhibited GSK3βphosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein.Our findings reveal a new crosstalk between inflammatory molecule A20 and“eat-me”signal in CRC,which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.
