Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic vir...Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.展开更多
基金funded by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018-013)by Natural Science Foundation Project of Sichuan(No.2022NSFSC0848)+1 种基金as well as supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD18007)The Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC202310005).
文摘Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
