Gastrointestinal(GI)cancers are a leading cause of cancer morbidity and mortality worldwide.Despite advances in treatment,cancer relapse remains a significant challenge,necessitating novel therapeutic strategies.In th...Gastrointestinal(GI)cancers are a leading cause of cancer morbidity and mortality worldwide.Despite advances in treatment,cancer relapse remains a significant challenge,necessitating novel therapeutic strategies.In this study,we engineered nanobody-based chimeric antigen receptor(CAR)natural killer(NK)cells targeting cadherin 17(CDH17)for the treatment of GI tumors.In addition,to enhance the efficacy of CAR-NK cells,we also incorporated CV1,a CD47–SIRPαaxis inhibitor,to evaluate the anti-tumor effect of this combination.We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner.CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models.Additionally,the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47–signal regulatory proteinα(SIRPα)axis inhibitor CV1,likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment.Collectively,our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers.The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy.Further investigations are warranted to speed up the clinical translation of these findings.展开更多
基金funded by the National Key Research and Development Program of China(2022YFC2303600)the Key Special Project of“Strategic Science and Technology Innovation Cooperation”from National Key R&D Program(2023YFE0204500,China)+11 种基金Shenzhen Science and Technology Innovation Committee(RCBS20210706092213007,China)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(CI2023D003,CI2021B014,and CI2023D008,China)the CACMS Innovation Fund(CI2023E002,CI2021A05101,and CI2021A05104,China)the Science and Technology Foundation of Shenzhen(JCYJ20210324115800001,JCYJ20210324113608023,and JCYJ20200109120205924,China)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Shenzhen Medical Research Fund(B2302051,China)the Shenzhen Science and Technology Innovation Committee(SZSTI)(RCYX20221008092950121,China)the National Natural Science Foundation of China(82373775,32101219,82103140,and 82304518)the Natural Science Foundation of Top Talent of SZTU(GDRC202125,China)the HUILAN Public Welfare,the Shenzhen Science and Technology Innovation Commission(JCYJ20200109120205924,China)Shenzhen Key Medical Discipline Construction Fund(SZXK046,China)Guangdong Basic and Applied Basic Research Foundation(2021A1515012164,2022A1515110745,and 2021A1515111188,China)International Science and Technology Cooperation for Shenzhen Technology Innovation Plan(GJHZ20200731095411034,China).
文摘Gastrointestinal(GI)cancers are a leading cause of cancer morbidity and mortality worldwide.Despite advances in treatment,cancer relapse remains a significant challenge,necessitating novel therapeutic strategies.In this study,we engineered nanobody-based chimeric antigen receptor(CAR)natural killer(NK)cells targeting cadherin 17(CDH17)for the treatment of GI tumors.In addition,to enhance the efficacy of CAR-NK cells,we also incorporated CV1,a CD47–SIRPαaxis inhibitor,to evaluate the anti-tumor effect of this combination.We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner.CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models.Additionally,the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47–signal regulatory proteinα(SIRPα)axis inhibitor CV1,likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment.Collectively,our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers.The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy.Further investigations are warranted to speed up the clinical translation of these findings.
