Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression...Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression during the ICI treatment.Thus,early identification of patients with no durable benefit would facilitate the clinical decision for these patients.In this prospective,multicenter study,101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients.At the date of cutoff,83 patients were eligible for ICI efficacy evaluation,with 56 patients having progress-free survival(PFS)over 6 months,which was defined as durable clinical benefit(DCB).A multimodal model was established by integrating normalized bTMB,early dynamic of ctDNA and thefirst RECIST response.This model could robustly predict DCB with area under the curve(AUC)of 0.878,sensitivity of 79.2%at 86.4%specificity(accuracy=80.0%).This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887,sensitivity of 94.7%at 85.3%specificity(accuracy=90.3%).Patients with higher predict scores had substantially longer PFS than those with lower scores(training cohort:median PFS 13.6 vs 4.2 months,P<0.001,HR=0.24;validation cohort:median PFS 11.0 vs 2.2 months,P<0.001,HR=0.17).Taken together,these results demonstrate that integrating early changes of ctDNA,normalized bTMB,and thefirst RECIST response can provide accurate,noninvasive,and early prediction of durable benefits for NSCLC patients treated with ICIs.Further prospective studies are warranted to validate thesefindings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.展开更多
After antigen stimulation, T cells preferentially increase aerobic glycolysis to meet the bioenergetic and biosynthetic demands of T cell activation, proliferation, and effector functions. Lactate, a by-product of gly...After antigen stimulation, T cells preferentially increase aerobic glycolysis to meet the bioenergetic and biosynthetic demands of T cell activation, proliferation, and effector functions. Lactate, a by-product of glycolysis, has been reported to function as an important energy source and signaling molecule. Here, we found that lactate anions are involved in cytokine production in Tcells after TCR activation. During ex vivo T cell activation, the addition of excess sodium lactate(Na L) increased the production of cytokines(such as IFNγ/IL-2/TNFα) more than the addition of sodium chloride(NaCl). This enhanced cytokine production was dependent on TCR/CD3 activation but not CD28 activation. In vivo, Na L treatment inhibited tumour growth in subcutaneously transplanted tumour models in a T cell-dependent manner, which was consistent with increased T cell cytokine production in the Na L treatment group compared to the Na Cl treatment group. Furthermore, a mechanistic experiment showed that this enhanced cytokine production was regulated by GAPDH-mediated post-transcriptional regulation. Taken together, our findings indicate a new regulatory mechanism involved in glycolysis that promotes T cell function.展开更多
基金supported by the National Natural Science Foundation of China(82030045 and 82241227 to S.L.)National Multi-disciplinary Treatment Project for Major Diseases(2020NMDTP to S.L.)+7 种基金Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education&Shanghai(CCTS-202204 and CCTS202304 to S.L.)Shanghai Chest Hospital Basic Research Project(2023YNKT-1 to S.L.)the Natural Science Foundation of Shanghai(22ZR1457500 to X.A.)the National Natural Science Foundation of China(82141117 to M.Z.)the Capital’s Funds for Health Improvement and Research(2022-2-1023 to M.Z.)WU JIEPING MEDICAL FOUNDATION(320.6750.2021-16-19 to M.Z.)Guangzhou Life oasis public service center Research and exchange program in thefield of health(1-35 to M.Z.)Beijing Xisike Clinical Oncology Research Foundation(Y-pierrefabre202101-0099 to M.Z.).
文摘Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression during the ICI treatment.Thus,early identification of patients with no durable benefit would facilitate the clinical decision for these patients.In this prospective,multicenter study,101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients.At the date of cutoff,83 patients were eligible for ICI efficacy evaluation,with 56 patients having progress-free survival(PFS)over 6 months,which was defined as durable clinical benefit(DCB).A multimodal model was established by integrating normalized bTMB,early dynamic of ctDNA and thefirst RECIST response.This model could robustly predict DCB with area under the curve(AUC)of 0.878,sensitivity of 79.2%at 86.4%specificity(accuracy=80.0%).This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887,sensitivity of 94.7%at 85.3%specificity(accuracy=90.3%).Patients with higher predict scores had substantially longer PFS than those with lower scores(training cohort:median PFS 13.6 vs 4.2 months,P<0.001,HR=0.24;validation cohort:median PFS 11.0 vs 2.2 months,P<0.001,HR=0.17).Taken together,these results demonstrate that integrating early changes of ctDNA,normalized bTMB,and thefirst RECIST response can provide accurate,noninvasive,and early prediction of durable benefits for NSCLC patients treated with ICIs.Further prospective studies are warranted to validate thesefindings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0507402 and 2016YFA0502202)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19000000).
文摘After antigen stimulation, T cells preferentially increase aerobic glycolysis to meet the bioenergetic and biosynthetic demands of T cell activation, proliferation, and effector functions. Lactate, a by-product of glycolysis, has been reported to function as an important energy source and signaling molecule. Here, we found that lactate anions are involved in cytokine production in Tcells after TCR activation. During ex vivo T cell activation, the addition of excess sodium lactate(Na L) increased the production of cytokines(such as IFNγ/IL-2/TNFα) more than the addition of sodium chloride(NaCl). This enhanced cytokine production was dependent on TCR/CD3 activation but not CD28 activation. In vivo, Na L treatment inhibited tumour growth in subcutaneously transplanted tumour models in a T cell-dependent manner, which was consistent with increased T cell cytokine production in the Na L treatment group compared to the Na Cl treatment group. Furthermore, a mechanistic experiment showed that this enhanced cytokine production was regulated by GAPDH-mediated post-transcriptional regulation. Taken together, our findings indicate a new regulatory mechanism involved in glycolysis that promotes T cell function.
