Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dM...Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dMMR)functions and poor response in patients with proficientMMR(pMMR).pMMRtumors are generally immunogenically“cold”,emphasizing combination strategies to turn the“cold”tumor“hot”to enhance the efficacy of ICIs.ATR inhibitors(ATRi)have been proven to cooperate with radiation to promote antitumor immunity,but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs.This study aimed to investigate the efficacy of combining ATRi,irradiation(IR),and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.Methods:The efficacy of combining ATRi,IR,and anti-PD-L1 antibodies was evaluated in CRC tumors.The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens.The mechanisms were explored via cell viability assay,flow cytometry,immunofluorescence,immunoblotting,co-immunoprecipitation,and real-time quantitative PCR in multiple murine and human CRC cell lines.Results:Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses.The mechanistic study demonstrated that IR+ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STINGp65 axis,via promoting SUMOylation of SHP1 at lysine 127.By boosting the STING signaling,IR+ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment,thus facilitating immunotherapy.Conclusions:The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsat展开更多
Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an u...Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.展开更多
基金Innovative Capacity Building Project of the Hubei Engineering Research Center for Radiotherapy and Radiation Protection of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Grant/Award Number:2018-420114-35-03-071705State Key Program of National Natural Science of China,Grant/Award Number:82130092National Natural Science Foundation of China,Grant/Award Numbers:81372664,81902619。
文摘Background:Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and programmed death-ligand 1(PD-L1)have shown a moderate response in colorectal cancer(CRC)with deficient mismatch repair(dMMR)functions and poor response in patients with proficientMMR(pMMR).pMMRtumors are generally immunogenically“cold”,emphasizing combination strategies to turn the“cold”tumor“hot”to enhance the efficacy of ICIs.ATR inhibitors(ATRi)have been proven to cooperate with radiation to promote antitumor immunity,but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs.This study aimed to investigate the efficacy of combining ATRi,irradiation(IR),and anti-PD-L1 antibodies in CRC mouse models with different microsatellite statuses.Methods:The efficacy of combining ATRi,IR,and anti-PD-L1 antibodies was evaluated in CRC tumors.The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens.The mechanisms were explored via cell viability assay,flow cytometry,immunofluorescence,immunoblotting,co-immunoprecipitation,and real-time quantitative PCR in multiple murine and human CRC cell lines.Results:Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti-PD-L1 therapy in mouse CRC models with different microsatellite statuses.The mechanistic study demonstrated that IR+ATRi could activate both the canonical cGAS-STING-pTBK1/pIRF3 axis by increasing cytosolic double-stranded DNA levels and the non-canonical STING signaling by attenuating SHP1-mediated inhibition of the TRAF6-STINGp65 axis,via promoting SUMOylation of SHP1 at lysine 127.By boosting the STING signaling,IR+ATRi induced type I interferon-related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment,thus facilitating immunotherapy.Conclusions:The combination of ATRi and IR could facilitate anti-PD-L1 therapy by promoting STING signaling in CRC models with different microsat
基金supported by the National Natural Science Foundation of China(Grant Nos.:81272488 and 81602802)the Shaanxi Province Innovation Capacity Support Program(Grant No.:2018TD-002).
文摘Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.
