Background:Programmed death 1(PD-1)blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer(NSCLC).Yet not all NSCLC patients benefit from this re...Background:Programmed death 1(PD-1)blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer(NSCLC).Yet not all NSCLC patients benefit from this regimen.This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods:We integrated clinical,genomic,and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone.We randomly assigned these patients into a discovery cohort(n=125),a validation cohort(n=82),and a control cohort(n=80).The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts.Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset.Results:A genomic variation signature,in which one or more of the 15 candidate genes were altered,was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts.Its predictive value held in multivariate analyses when adjusted for baseline parameters,programmed cell death ligand 1(PD-L1)expression level,and tumor mutation burden.Moreover,applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination.Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates,indicating an immune-desert tumor microenvironment.Conclusion:These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.展开更多
Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 m...Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 mm^(3))and medium distant(100 mm^(3))EG7 lymphomas engineered to express ovalbumin(OVA)as a nominal tumor antigen.We established experimental protocols including IRE alone and IRE combined with Toll-like receptor(TLR)3/9 agonists(poly I:C/CpG)(IRE+pIC/CpG),PD-1 blockade(IRE+PD-1 blockade),or both(IRE+Combo)to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment(TME).We demonstrated that IRE alone simulated very weak OVA-specific CD8^(+)T cell responses and did not inhibit primary tumor growth.IRE+pIC/CpG synergistically stimulated more efficient OVA-specific CD8^(+)T cell responses and primary tumor growth inhibition than IRE+PD-1 blockade.IRE+pIC/CpG played a major role in the modulation of immune cell profiles but a minor role in the downregulation of PD-L1 expression in the TME and vice versa for IRE+PD-1 blockade.IRE+Combo cooperatively induced potent OVA-specific CD8^(+)T cell immunity and rescued exhausted intratumoral CD8^(+)T cells,leading to eradication of not only primary tumors but also untreated concomitant distant tumors and lung metastases.IRE+Combo efficiently modulated immune cell profiles,as evidenced by reductions in immunotolerant type-2(M2)macrophages,myeloid-derived suppressor-cells,plasmacytoid dendritic cells,and regulatory T cells and by increases in immunogenic M1 macrophages,CD169^(+)macrophages,type-1 conventional dendritic cells,and CD8^(+)T cells,leading to conversion of immunotolerance in not only primary TMEs but also untreated distant TMEs.IRE+Combo also showed effective therapeutic effects in two breast cancer models.Therefore,our results suggest that IRE+Combo is a promising strategy to improve IRE ablation therapy in cancer.展开更多
Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of im...Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.展开更多
During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is...During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82102859,82172869,82141101,82272875,and 12126605)the Shanghai Rising-Star Program(Nos.23QA1408000 and 22QA1407800)+1 种基金the Shanghai"Rising Stars of Medical Talent"Youth Development Program Youth Medical Talents—Specialist Program,the Original Exploration Project of Shanghai Natural Science Foundation(No.23ZR1480600)the Health and Family Planning Commission of Shanghai Municipality(No.20224Y0067)
文摘Background:Programmed death 1(PD-1)blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer(NSCLC).Yet not all NSCLC patients benefit from this regimen.This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods:We integrated clinical,genomic,and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone.We randomly assigned these patients into a discovery cohort(n=125),a validation cohort(n=82),and a control cohort(n=80).The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts.Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset.Results:A genomic variation signature,in which one or more of the 15 candidate genes were altered,was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts.Its predictive value held in multivariate analyses when adjusted for baseline parameters,programmed cell death ligand 1(PD-L1)expression level,and tumor mutation burden.Moreover,applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination.Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates,indicating an immune-desert tumor microenvironment.Conclusion:These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.
文摘Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated.We developed a mouse model bearing large primary(300 mm^(3))and medium distant(100 mm^(3))EG7 lymphomas engineered to express ovalbumin(OVA)as a nominal tumor antigen.We established experimental protocols including IRE alone and IRE combined with Toll-like receptor(TLR)3/9 agonists(poly I:C/CpG)(IRE+pIC/CpG),PD-1 blockade(IRE+PD-1 blockade),or both(IRE+Combo)to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment(TME).We demonstrated that IRE alone simulated very weak OVA-specific CD8^(+)T cell responses and did not inhibit primary tumor growth.IRE+pIC/CpG synergistically stimulated more efficient OVA-specific CD8^(+)T cell responses and primary tumor growth inhibition than IRE+PD-1 blockade.IRE+pIC/CpG played a major role in the modulation of immune cell profiles but a minor role in the downregulation of PD-L1 expression in the TME and vice versa for IRE+PD-1 blockade.IRE+Combo cooperatively induced potent OVA-specific CD8^(+)T cell immunity and rescued exhausted intratumoral CD8^(+)T cells,leading to eradication of not only primary tumors but also untreated concomitant distant tumors and lung metastases.IRE+Combo efficiently modulated immune cell profiles,as evidenced by reductions in immunotolerant type-2(M2)macrophages,myeloid-derived suppressor-cells,plasmacytoid dendritic cells,and regulatory T cells and by increases in immunogenic M1 macrophages,CD169^(+)macrophages,type-1 conventional dendritic cells,and CD8^(+)T cells,leading to conversion of immunotolerance in not only primary TMEs but also untreated distant TMEs.IRE+Combo also showed effective therapeutic effects in two breast cancer models.Therefore,our results suggest that IRE+Combo is a promising strategy to improve IRE ablation therapy in cancer.
基金supported in part by NIH/NCI 1R01CA264102-01(D.Z.)Wake Forest Comprehensive Cancer Center P30 CA01219740.A.A.H.is supported by funding from the Department of Veteran’s Affairs(No.2I01BX002559-07)from the National Institutes of Health(No.1R01CA244212-01A1).
文摘Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.
文摘During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
