Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore...Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.展开更多
T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge ...T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge provides the foundation for chimeric antigen receptor T cell(CAR-T cell)technology,by which T cells are redirected in a major histocompatibility complex-unrestricted manner.TCR and CAR signaling plays a critical role in determining the T cell state,including exhaustion and memory.Given its artificial nature,CARs might affect or rewire signaling differently than TCRs.A better understanding of CAR signal transduction would greatly facilitate improvements to CAR-T cell technology and advance its usefulness in clinical practice.Herein,we systematically review the knowns and unknowns of TCR and CAR signaling,from the contact of receptors and antigens,proximal signaling,immunological synapse formation,and late signaling outcomes.Signaling through different T cell subtypes and how signaling is translated into practice are also discussed.展开更多
基金funded by the key R&D Project of Hubei Province(Social Development),China(2022BCA018)the Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),China(2022KF16)to Kanghong Hu.
文摘Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.
文摘T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge provides the foundation for chimeric antigen receptor T cell(CAR-T cell)technology,by which T cells are redirected in a major histocompatibility complex-unrestricted manner.TCR and CAR signaling plays a critical role in determining the T cell state,including exhaustion and memory.Given its artificial nature,CARs might affect or rewire signaling differently than TCRs.A better understanding of CAR signal transduction would greatly facilitate improvements to CAR-T cell technology and advance its usefulness in clinical practice.Herein,we systematically review the knowns and unknowns of TCR and CAR signaling,from the contact of receptors and antigens,proximal signaling,immunological synapse formation,and late signaling outcomes.Signaling through different T cell subtypes and how signaling is translated into practice are also discussed.
