Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fet...Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.展开更多
AIM： To observe the presence and expression of indoleamine 2,3-dioxygenase（IDO） during the corneal immunity to Aspergillus fumigatus（A. fumigatus） in the murine models.·METHODS： The murine model of fungal k...AIM： To observe the presence and expression of indoleamine 2,3-dioxygenase（IDO） during the corneal immunity to Aspergillus fumigatus（A. fumigatus） in the murine models.·METHODS： The murine model of fungal keratitis was established by smearing with colonies of A. fumigatus after scraping central epithelium of cornea and covering with contact lenses in C57BL/6 mice. The mice were randomly divided into control group, sham group and A.fumigatus keratitis group. The cornea was monitored daily using a slit lamp and recorded disease score after infection. Corneal lesion was detected by immunofluorescence staining. IDO m RNA and protein were also detected by quantitative reverse transcription-polymerase chain reaction（q RT-PCR） and Western blot.· RESULTS： The disease score and slit lamp photography indicated that disease severity was consistent with corneal inflammation in the murine models, and the disease scores in A. fumigatus keratitis group were obviously higher than those in the sham group. By immunofluorescence staining, IDO was mainly localized in corneal epithelium and stroma in the murine corneal tissues with A. fumigatus keratitis. Compared with the sham group, IDO m RNA expression was significantly enhanced in corneal epithelium infected by A. fumigatus. Furthermore, IDO protein expression detected by Western blot was in accord with transcript levels of IDO m RNA measured by q RT-PCR. IDO protein expression was enhanced after A. fumigatus infection compared with the sham group.·CONCLUSION： IDO is detected in corneal epithelium and stroma locally, which indicates IDO takes part in the pathogenesis of A. fumigatus keratitis and plays a key role in immune regulation at the early stage.展开更多
AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratiti...AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratitis were established by inoculating hyphae of A.fumigatus evenly on the corneas.The clinical scores and inflammatory cytokines expression were measured respectively on the 1^(st), 3^(th), 5^(th) day after infection.The 1-MT(1 mg/m L) was administered by gavage to exert an inhibitory effect on IDO during infection.The mice were divided into control group, 1-MT group, A.fumigatus(A.F.) group, and 1-MT+A.F.groups.The corneas were monitored by slit lamp microscopy, and recorded disease scores in 3 d after infection.Myeloperoxidase(MPO) assay was done to evaluate the neutrophils infiltration.Immunofluorescence staining was used to detect the recruitment of neutrophils in murine corneas.The m RNA of inflammatory cytokines was measured with reverse transcription-polymerase chain reaction(RT-PCR).RESULTS: The corneal inflammation and the clinical score reached the peak on the 3;day after the corneal infection.The m RNA of inflammatory cytokines of the A.F.group reached the highest on the 3;day after the infection accordingly.Meanwhile, the results of slit light photography indicated that inhibitors of IDO made inflammation more serious contrasted with the A.F.group on the 3;day.Besides, imunofluorescence staining and MPO indicated that 1-MT enhanced the recruitment, infiltration and chemotaxis of neutrophils obviously in contrast to the A.F.group.RT-PCR indicated that 1-MT increased the expression of CXCL-1, ICAM-1, IL-1β, and IL-8 significantly.CONCLUSION: IDO participates in the pathogenesis of A.fumigatus keratitis and plays an important role in inducing immune protection by inhibiting neutrophils-related inflammatory reaction and suppressing recruitment and chemotaxis of the neutrophils.展开更多
Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp)catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of...Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp)catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penilesquamous cell carcinoma (PSCC) and explored their clinical significance.Methods: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn)were examined in 114 PSCC patients by immunohistonchemistry and solid-phaseextraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were definedby principal component analysis. The correlativity was assessed by Pearson’s correlation analysis.Results: The expression level of IDO1 in PSCC cells was positively correlatedwith serum Kyn concentration and Kyn/Trp radio (KTR;both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 upregulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008and 0.032, respectively). High expression level of IDO1 in cancer cells and serumKTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926;95% confidence interval [CI],2.458-19.068;P < 0.001) and pathologic grade (HR, 2.194;95% CI, 1.021-4.529;P = 0.038), only serum KTR (HR, 2.780;95% CI, 1.066-7.215;P = 0.036) was anindependent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-𝛾 (IFN𝛾, P < 0.001) and immunosuppressivemarkers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2;all P < 0.05), and the infiltration ofimmune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumorassociated macrophages, and myeloid-derived suppressor cells;all P < 0.001) inPSCC tissues. Furthermore, the expression of IDO1 was induced by IFN𝛾 in a dosedependent manner in PSCC cells.Conclusions: IFN𝛾-induced IDO1 plays a crucial role in immunoediting andimmunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1catabolic activity, can be utilized as an independent prognostic factor for PSCC.展开更多
Background Increasing evidence suggests that, by the production of indoleamine 2, 3-dioxygenase （IDO）, dendritic cells （DC） may reduce the activity of T lymphocytes and inhibit T lymphocyte proliferation-induced i...Background Increasing evidence suggests that, by the production of indoleamine 2, 3-dioxygenase （IDO）, dendritic cells （DC） may reduce the activity of T lymphocytes and inhibit T lymphocyte proliferation-induced immune tolerance.One promising way is inspired by increasing IDO expression in DG cells for immune tolerance after transplantation. The aim of this work was to examine the effect of interferon-y （IFN-γ） on the expression of IDO by DC.Methods Spleen-derived rat DCs were cultured and induced by cytokines, and the expression of OX62 and surface molecules CD80 and CD86 were measured with flow cytometry. After the DCs were induced by IFN-γ at different concentrations （0, 100, 300, 500 U/ml）, the expression levels of IDO mRNA were measured with real-time PCR, and the expression levels of IDO protein in DCs were measured with Western blotting. The allogeneic mixed lymphocyte reaction （MLR） was used to test the effects of DCs incubated with different concentrations of IFN-γ on allogeneic T lymphocyte proliferation.Results Under the microscope, the DCs induced by IFN-γ showed a typical dendritic morphology. The expression rate of OX62 was above 80% and the positive expression rates of CD80 and CD86 were both about 80%. The expressions of IDO mRNA and IDO protein increased gradually with the increase of IFN-γ concentration, showing statistical significance in the differences between the groups （P 〈0.05）. Compared with the control DC, the DC incubated with IFN-γ had a notable decrease in allostimulatory activity （P 〈0.05）. With the increasing IFN-γ concentration, the T lymphocyte proliferation decreased, and the difference between the groups was also statistically significant （P 〈0.05）.Conclusions The highly purified spleen derived rat DCs can be successfully acquired through the improved adhesion in-vitro method. IFN-γ can induce increased expression of IDO in spleen-derived rat DCs and reduce the spleen DCs＇ capacity to stimulate the proliferation of allogeneic T cells.展开更多
Mesenchymal stem cells have been previously shown to exert an immunomodulatory function. The present study sought to investigate the effects of multipotential human adipose tissue-derived mesenchymal stem cells （hAdM...Mesenchymal stem cells have been previously shown to exert an immunomodulatory function. The present study sought to investigate the effects of multipotential human adipose tissue-derived mesenchymal stem cells （hAdMSCs） on disease progression and cytokine expression in Lewis rats with experimental autoimmune encephalomyelitis （EAE） induced by myelin basic protein. The duration of EAE paralysis in the group treated on day 7 posfimmunization with 5 × 10^6 hAdMSCs was significantly reduced compared with the vehicle-treated controls and the 1 x 106 hAdMSC- treated group. The duration of EAE paralysis in the groups treated with 5 × 10^6 hAdMSCs on both day 1 and day 7 postimmunization was significantly reduced compared with the vehicle-treated controls and the groups treated with 5 × 10^6 hAdMSCs on both day 7 and day 10 postimmunization. The mRNA expression of interleukin-10 and indoleamine 2, 3-dioxygenase was significantly decreased in the hAdMSC-treated group compared with the vehicle-treated group. These findings suggest that the ameliorative effects of hAdMSCs on EAE symptoms operate in a dose- and time-dependent manner and can be mediated in part by the ample production of anti-inflammatory cytokines.展开更多
Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challeng...Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.展开更多
文摘Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs), and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC func- tions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflam- matory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regu- lated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.
基金Supported by the National Natural Science Foundation of China(No.81170825No.81470609)+2 种基金Specialized Research Fund for the Doctoral Program of Higher Education(No.20123706110003)The Youth Natural Science Foundation of Shandong Province(No.ZR2013HQ007)The Key Project of Natural Science Foundation of Shandong Province(No.ZR2012HZ001)
文摘AIM： To observe the presence and expression of indoleamine 2,3-dioxygenase（IDO） during the corneal immunity to Aspergillus fumigatus（A. fumigatus） in the murine models.·METHODS： The murine model of fungal keratitis was established by smearing with colonies of A. fumigatus after scraping central epithelium of cornea and covering with contact lenses in C57BL/6 mice. The mice were randomly divided into control group, sham group and A.fumigatus keratitis group. The cornea was monitored daily using a slit lamp and recorded disease score after infection. Corneal lesion was detected by immunofluorescence staining. IDO m RNA and protein were also detected by quantitative reverse transcription-polymerase chain reaction（q RT-PCR） and Western blot.· RESULTS： The disease score and slit lamp photography indicated that disease severity was consistent with corneal inflammation in the murine models, and the disease scores in A. fumigatus keratitis group were obviously higher than those in the sham group. By immunofluorescence staining, IDO was mainly localized in corneal epithelium and stroma in the murine corneal tissues with A. fumigatus keratitis. Compared with the sham group, IDO m RNA expression was significantly enhanced in corneal epithelium infected by A. fumigatus. Furthermore, IDO protein expression detected by Western blot was in accord with transcript levels of IDO m RNA measured by q RT-PCR. IDO protein expression was enhanced after A. fumigatus infection compared with the sham group.·CONCLUSION： IDO is detected in corneal epithelium and stroma locally, which indicates IDO takes part in the pathogenesis of A. fumigatus keratitis and plays a key role in immune regulation at the early stage.
基金Supported by the National Natural Science Foundation of China (No.81870632)the Youth National Natural Science Foundation of China (No.81700800)the Natural Science Foundation of Shandong Province (No.ZR2017MH008)。
文摘AIM: To explore the effect of indoleamine 2,3-dioxygenase(IDO) on recruitment and chemotaxis function of neutrophils in Aspergillus fumigatus(A.fumigatus) keratitis.METHODS: C57BL/6 mice models of A.fumigatus keratitis were established by inoculating hyphae of A.fumigatus evenly on the corneas.The clinical scores and inflammatory cytokines expression were measured respectively on the 1^(st), 3^(th), 5^(th) day after infection.The 1-MT(1 mg/m L) was administered by gavage to exert an inhibitory effect on IDO during infection.The mice were divided into control group, 1-MT group, A.fumigatus(A.F.) group, and 1-MT+A.F.groups.The corneas were monitored by slit lamp microscopy, and recorded disease scores in 3 d after infection.Myeloperoxidase(MPO) assay was done to evaluate the neutrophils infiltration.Immunofluorescence staining was used to detect the recruitment of neutrophils in murine corneas.The m RNA of inflammatory cytokines was measured with reverse transcription-polymerase chain reaction(RT-PCR).RESULTS: The corneal inflammation and the clinical score reached the peak on the 3;day after the corneal infection.The m RNA of inflammatory cytokines of the A.F.group reached the highest on the 3;day after the infection accordingly.Meanwhile, the results of slit light photography indicated that inhibitors of IDO made inflammation more serious contrasted with the A.F.group on the 3;day.Besides, imunofluorescence staining and MPO indicated that 1-MT enhanced the recruitment, infiltration and chemotaxis of neutrophils obviously in contrast to the A.F.group.RT-PCR indicated that 1-MT increased the expression of CXCL-1, ICAM-1, IL-1β, and IL-8 significantly.CONCLUSION: IDO participates in the pathogenesis of A.fumigatus keratitis and plays an important role in inducing immune protection by inhibiting neutrophils-related inflammatory reaction and suppressing recruitment and chemotaxis of the neutrophils.
基金National Natural Science Foundation of China,Grant/Award Number:81772755
文摘Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp)catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penilesquamous cell carcinoma (PSCC) and explored their clinical significance.Methods: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn)were examined in 114 PSCC patients by immunohistonchemistry and solid-phaseextraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were definedby principal component analysis. The correlativity was assessed by Pearson’s correlation analysis.Results: The expression level of IDO1 in PSCC cells was positively correlatedwith serum Kyn concentration and Kyn/Trp radio (KTR;both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 upregulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008and 0.032, respectively). High expression level of IDO1 in cancer cells and serumKTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926;95% confidence interval [CI],2.458-19.068;P < 0.001) and pathologic grade (HR, 2.194;95% CI, 1.021-4.529;P = 0.038), only serum KTR (HR, 2.780;95% CI, 1.066-7.215;P = 0.036) was anindependent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-𝛾 (IFN𝛾, P < 0.001) and immunosuppressivemarkers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2;all P < 0.05), and the infiltration ofimmune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumorassociated macrophages, and myeloid-derived suppressor cells;all P < 0.001) inPSCC tissues. Furthermore, the expression of IDO1 was induced by IFN𝛾 in a dosedependent manner in PSCC cells.Conclusions: IFN𝛾-induced IDO1 plays a crucial role in immunoediting andimmunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1catabolic activity, can be utilized as an independent prognostic factor for PSCC.
基金This work was supported by grants from the Shanxi Provincial Natural Science Foundation （No. 2009011052-2） and Scientific Research Foundation for Returned Scholars of the Ministry of Education of China （No. 99）.
文摘Background Increasing evidence suggests that, by the production of indoleamine 2, 3-dioxygenase （IDO）, dendritic cells （DC） may reduce the activity of T lymphocytes and inhibit T lymphocyte proliferation-induced immune tolerance.One promising way is inspired by increasing IDO expression in DG cells for immune tolerance after transplantation. The aim of this work was to examine the effect of interferon-y （IFN-γ） on the expression of IDO by DC.Methods Spleen-derived rat DCs were cultured and induced by cytokines, and the expression of OX62 and surface molecules CD80 and CD86 were measured with flow cytometry. After the DCs were induced by IFN-γ at different concentrations （0, 100, 300, 500 U/ml）, the expression levels of IDO mRNA were measured with real-time PCR, and the expression levels of IDO protein in DCs were measured with Western blotting. The allogeneic mixed lymphocyte reaction （MLR） was used to test the effects of DCs incubated with different concentrations of IFN-γ on allogeneic T lymphocyte proliferation.Results Under the microscope, the DCs induced by IFN-γ showed a typical dendritic morphology. The expression rate of OX62 was above 80% and the positive expression rates of CD80 and CD86 were both about 80%. The expressions of IDO mRNA and IDO protein increased gradually with the increase of IFN-γ concentration, showing statistical significance in the differences between the groups （P 〈0.05）. Compared with the control DC, the DC incubated with IFN-γ had a notable decrease in allostimulatory activity （P 〈0.05）. With the increasing IFN-γ concentration, the T lymphocyte proliferation decreased, and the difference between the groups was also statistically significant （P 〈0.05）.Conclusions The highly purified spleen derived rat DCs can be successfully acquired through the improved adhesion in-vitro method. IFN-γ can induce increased expression of IDO in spleen-derived rat DCs and reduce the spleen DCs＇ capacity to stimulate the proliferation of allogeneic T cells.
文摘Mesenchymal stem cells have been previously shown to exert an immunomodulatory function. The present study sought to investigate the effects of multipotential human adipose tissue-derived mesenchymal stem cells （hAdMSCs） on disease progression and cytokine expression in Lewis rats with experimental autoimmune encephalomyelitis （EAE） induced by myelin basic protein. The duration of EAE paralysis in the group treated on day 7 posfimmunization with 5 × 10^6 hAdMSCs was significantly reduced compared with the vehicle-treated controls and the 1 x 106 hAdMSC- treated group. The duration of EAE paralysis in the groups treated with 5 × 10^6 hAdMSCs on both day 1 and day 7 postimmunization was significantly reduced compared with the vehicle-treated controls and the groups treated with 5 × 10^6 hAdMSCs on both day 7 and day 10 postimmunization. The mRNA expression of interleukin-10 and indoleamine 2, 3-dioxygenase was significantly decreased in the hAdMSC-treated group compared with the vehicle-treated group. These findings suggest that the ameliorative effects of hAdMSCs on EAE symptoms operate in a dose- and time-dependent manner and can be mediated in part by the ample production of anti-inflammatory cytokines.
基金supported by the National Natural Science Foundation of China(Nos.81920108001 and 81870007)Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.
文摘Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.
