BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhi...BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.展开更多
In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(T...In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.展开更多
Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumo...Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumor therapies,such as chemotherapy,radiotherapy,and targeted therapy,have limited efficacy in the treatment of advanced synchronous multiple primary NSCLC.Immunotherapy is considered the standard of care for advanced or recurrent NSCLC,however,approximately 60%of patients develop primary or secondary resistance to treatment.There are no standard recommendations for overcoming immune resistance.We describe a case of simultaneous multiple primary NSCLC in a patient who received programmed death factor-1(PD-1)inhibitor monotherapy and developed brain metastases.After receiving second-line treatment with a combination of another PD-1 inhibitor,pemetrexed,and bevacizumab,the patient achieved complete remission,although they experienced grade 3 immune-related adverse reactions.Immune re-challenge is safe and feasible,and choosing a synergistic combination regimen is one of the options to overcome immune resistance.A larger sample size is needed to confirm the effectiveness and safety of this strategy in patients with NSCLC resistant to prior PD-1 inhibitors.展开更多
Introduction: Conventional radiotherapy or chemotherapy is ineffective in the treatment of recurrent and metastatic cervical cancer. In recent years, immunotherapy has shown promise in the treatment of various solid t...Introduction: Conventional radiotherapy or chemotherapy is ineffective in the treatment of recurrent and metastatic cervical cancer. In recent years, immunotherapy has shown promise in the treatment of various solid tumours, including cervical cancer. The overall response rate of the PD-1/PD-L1 inhibitor in cervical cancer is 14% - 27%, and when combined with radiotherapy or conventional chemotherapy, the overall response rate can be further improved. Case presentation: We report here a case of a 49-year-old female patient presenting with two metastatic lesions of cervical cancer after postoperative radiotherapy, the first was located in the para-aortic region and the second in the presacral region. The enlarged para-aortic lymph nodes had not previously received radiotherapy, while the enlarged presacral lymph nodes had previously received postoperative radiotherapy. Treatment results showed that the recurrent presacral mass did not respond to the PD-1 inhibitor (camrelizumab) alone, whereas the metastatic para-aortic lymph nodes responded favourably to camrelizumab combined with low-intensity radiotherapy. Conclusion: PD1/PD-L1 inhibitors combined with radiotherapy should make it possible to overcome the bottleneck of conventional radiotherapy, improve patient prognosis or achieve better local control rates with lower radiotherapy doses.展开更多
BACKGROUND PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer.In this case report,the combination of a PD-1 inhibitor and fruq...BACKGROUND PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer.In this case report,the combination of a PD-1 inhibitor and fruquintinib demonstrated good efficacy in patients with MSI-H colorectal cancer.CASE SUMMARY The patient was a young man in his 30s who had MSI-H type colon cancer.The patient underwent four cycles of neoadjuvant therapy with a PD-1 inhibitor combined with fruquintinib before surgery,resulting in regression of the mass and a successful surgery.CONCLUSION Some patients with colorectal cancer have the MSI-H type,and the first-line chemotherapy regimen is not effective.However,PD-1 monoclonal antibody immunotherapy has a good therapeutic effect,which can be improved by combination therapy with fruquintinib.We recommend that patients with a history of colon or rectal cancer receive universal MSI testing;then,neoadjuvant therapy should be used.展开更多
Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a m...Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.展开更多
Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated t...Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy.Hence,we investigated whether RT enhances the efficacy of anti-programmed death receptor-1(PD-1)inhibitors in advanced HCC in real-world practice.Methods:Between August 2018 and June 2021,172 patients with advanced primary HCC were enrolled in the tertiary center(Zhongshan Hospital of Fudan University);95 were treated with a combination of RT and the inhibitor of PD-1(RT-PD1 cohort),and 77 were administered anti-PD-1 therapy(PD1 cohort).The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT.Propensity score matching for bias reduction was used to evaluate the clinical outcomes.Results:Among 71 propensity-matched pairs,median progression-free survival was 5.7 months in the RT-PD1 cohort vs.2.9 months in the PD1 cohort(P<0.001).Median overall survival was 20.9 months in the RT-PD1 cohort vs.11.2 months in the PD1 cohort(P=0.018).Compared with patients in the PD1 cohort,patients in the RT-PD1 cohort had significantly higher objective response rates(40.8%,29/71 vs.19.7%,14/71,P=0.006)and disease control rates(62.0%,44/71 vs.31.0%,22/71,P<0.001).The incidences of toxic effects were not significantly different between the two cohorts.Conclusions:RT plus anti-PD-1 therapy is well tolerated.RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.展开更多
目的:探讨血小板与白细胞比值(platelet and white blood cells ratio, PWR)、血小板与淋巴细胞比值(platelet and lymphocyte ratio, PLR)、中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio, NLR)以及尿白细胞计数(urinary l...目的:探讨血小板与白细胞比值(platelet and white blood cells ratio, PWR)、血小板与淋巴细胞比值(platelet and lymphocyte ratio, PLR)、中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio, NLR)以及尿白细胞计数(urinary leucocyte count, ULEU)与接受PD-1抑制剂治疗晚期尿路上皮癌(urothelial carcinoma, UC)患者预后的关系。方法:收集78例接受PD-1抑制剂治疗晚期UC患者的临床资料,利用Kaplan-Meier法计算生存率和Log-rank检验比较不同组间的生存差异,同时采用COX回归分析预后影响因素。结果:低PLR组与高PLR组的1年生存率分别为71.98%和47.63%,差异有统计学意义(P<0.05);低NLR组与高NLR组的1年生存率分别为71.36%和48.15%,差异有统计学意义(P<0.05);PWR高低两组和ULEU状态预测UC患者生存率无显著性差异(P>0.05)。单因素回归分析结果显示,N分期、M分期、TNM分期、远处转移个数、PLR、NLR是影响晚期UC患者生存情况的危险因素(P<0.05)。多因素回归分析显示,PLR是影响接受PD-1抑制剂治疗的UC患者预后的独立因素。结论:PLR、NLR为影响接受PD-1抑制剂治疗晚期UC患者预后的独立因素,PLR高值组和NLR高值组患者的预后较PLR低值组和NLR低值组的患者差。展开更多
The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment(TIME).This study aimed to mechanistically assess whether Chang Wei Qing(CWQ)Decoction can enh...The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment(TIME).This study aimed to mechanistically assess whether Chang Wei Qing(CWQ)Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy.PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repairdeficient/microsatellite instability-high(dMMR/MSI-H)colorectal cancer(CRC),rather than those with mismatch repairproficient/microsatellite stable(pMMR/MSS)CRC.Hence,immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients.Flow cytometry was used to analyze T-lymphocytes in tumors from mice.Western blot was used to measure the expression of PD-L1 protein in mouse tumors.The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry.16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice.Subsequently,Spearman’s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes.The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins.In vivo,CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+and PD-1+CD8+T cells in tumors.Additionally,the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone.CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes,and Actinobacteria.Additionally,the proportion of infiltrated CD8+PD-1+,CD8+,and CD3+T cells were found to be positively correlated with the abundance of Akkermansia.Accordingly,CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.展开更多
基金The study was reviewed and approved by the Beijing Ditan Hospital,Capital Medical University Institutional Review Board(Approval No.JDLC 2021-003-02).
文摘BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.
基金The National Natural Science Foundation of China,No.82104525The Natural Science Foundation of the Jiangsu Higher Education Institutions of China,No.21KJB360009.
文摘In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.
文摘Lung cancer is a malignant tumor with high incidence and mortality rates in China and worldwide.Approximately 10%of these diseases are caused by multiple primary non-small cell lung cancers(NSCLC).Traditional antitumor therapies,such as chemotherapy,radiotherapy,and targeted therapy,have limited efficacy in the treatment of advanced synchronous multiple primary NSCLC.Immunotherapy is considered the standard of care for advanced or recurrent NSCLC,however,approximately 60%of patients develop primary or secondary resistance to treatment.There are no standard recommendations for overcoming immune resistance.We describe a case of simultaneous multiple primary NSCLC in a patient who received programmed death factor-1(PD-1)inhibitor monotherapy and developed brain metastases.After receiving second-line treatment with a combination of another PD-1 inhibitor,pemetrexed,and bevacizumab,the patient achieved complete remission,although they experienced grade 3 immune-related adverse reactions.Immune re-challenge is safe and feasible,and choosing a synergistic combination regimen is one of the options to overcome immune resistance.A larger sample size is needed to confirm the effectiveness and safety of this strategy in patients with NSCLC resistant to prior PD-1 inhibitors.
文摘Introduction: Conventional radiotherapy or chemotherapy is ineffective in the treatment of recurrent and metastatic cervical cancer. In recent years, immunotherapy has shown promise in the treatment of various solid tumours, including cervical cancer. The overall response rate of the PD-1/PD-L1 inhibitor in cervical cancer is 14% - 27%, and when combined with radiotherapy or conventional chemotherapy, the overall response rate can be further improved. Case presentation: We report here a case of a 49-year-old female patient presenting with two metastatic lesions of cervical cancer after postoperative radiotherapy, the first was located in the para-aortic region and the second in the presacral region. The enlarged para-aortic lymph nodes had not previously received radiotherapy, while the enlarged presacral lymph nodes had previously received postoperative radiotherapy. Treatment results showed that the recurrent presacral mass did not respond to the PD-1 inhibitor (camrelizumab) alone, whereas the metastatic para-aortic lymph nodes responded favourably to camrelizumab combined with low-intensity radiotherapy. Conclusion: PD1/PD-L1 inhibitors combined with radiotherapy should make it possible to overcome the bottleneck of conventional radiotherapy, improve patient prognosis or achieve better local control rates with lower radiotherapy doses.
文摘BACKGROUND PD-1 inhibitors in combination with fruquintinib have not previously been reported as neoadjuvant therapy for patients with colorectal cancer.In this case report,the combination of a PD-1 inhibitor and fruquintinib demonstrated good efficacy in patients with MSI-H colorectal cancer.CASE SUMMARY The patient was a young man in his 30s who had MSI-H type colon cancer.The patient underwent four cycles of neoadjuvant therapy with a PD-1 inhibitor combined with fruquintinib before surgery,resulting in regression of the mass and a successful surgery.CONCLUSION Some patients with colorectal cancer have the MSI-H type,and the first-line chemotherapy regimen is not effective.However,PD-1 monoclonal antibody immunotherapy has a good therapeutic effect,which can be improved by combination therapy with fruquintinib.We recommend that patients with a history of colon or rectal cancer receive universal MSI testing;then,neoadjuvant therapy should be used.
基金supported by the National Natural Science Foundation of China under contract No.82203000the Shandong Provincial Natural Science Foundation under contract No.ZR202111120102the Taishan Scholars Program of Shandong Province(tsqnz20221164).
文摘Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.
基金National Natural Science Foundation of China(No.82073479)
文摘Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising strategy.In preclinical studies,irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy.Hence,we investigated whether RT enhances the efficacy of anti-programmed death receptor-1(PD-1)inhibitors in advanced HCC in real-world practice.Methods:Between August 2018 and June 2021,172 patients with advanced primary HCC were enrolled in the tertiary center(Zhongshan Hospital of Fudan University);95 were treated with a combination of RT and the inhibitor of PD-1(RT-PD1 cohort),and 77 were administered anti-PD-1 therapy(PD1 cohort).The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT.Propensity score matching for bias reduction was used to evaluate the clinical outcomes.Results:Among 71 propensity-matched pairs,median progression-free survival was 5.7 months in the RT-PD1 cohort vs.2.9 months in the PD1 cohort(P<0.001).Median overall survival was 20.9 months in the RT-PD1 cohort vs.11.2 months in the PD1 cohort(P=0.018).Compared with patients in the PD1 cohort,patients in the RT-PD1 cohort had significantly higher objective response rates(40.8%,29/71 vs.19.7%,14/71,P=0.006)and disease control rates(62.0%,44/71 vs.31.0%,22/71,P<0.001).The incidences of toxic effects were not significantly different between the two cohorts.Conclusions:RT plus anti-PD-1 therapy is well tolerated.RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.
文摘目的:探讨血小板与白细胞比值(platelet and white blood cells ratio, PWR)、血小板与淋巴细胞比值(platelet and lymphocyte ratio, PLR)、中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio, NLR)以及尿白细胞计数(urinary leucocyte count, ULEU)与接受PD-1抑制剂治疗晚期尿路上皮癌(urothelial carcinoma, UC)患者预后的关系。方法:收集78例接受PD-1抑制剂治疗晚期UC患者的临床资料,利用Kaplan-Meier法计算生存率和Log-rank检验比较不同组间的生存差异,同时采用COX回归分析预后影响因素。结果:低PLR组与高PLR组的1年生存率分别为71.98%和47.63%,差异有统计学意义(P<0.05);低NLR组与高NLR组的1年生存率分别为71.36%和48.15%,差异有统计学意义(P<0.05);PWR高低两组和ULEU状态预测UC患者生存率无显著性差异(P>0.05)。单因素回归分析结果显示,N分期、M分期、TNM分期、远处转移个数、PLR、NLR是影响晚期UC患者生存情况的危险因素(P<0.05)。多因素回归分析显示,PLR是影响接受PD-1抑制剂治疗的UC患者预后的独立因素。结论:PLR、NLR为影响接受PD-1抑制剂治疗晚期UC患者预后的独立因素,PLR高值组和NLR高值组患者的预后较PLR低值组和NLR低值组的患者差。
基金the Health System Innovation Project of Shanghai Putuo Science and Technology Commission(No.ptkwws202002)the Traditional Chinese Medicine Clinical Key Specialty Construction Project of Shanghai Putuo District(No.ptzyzk2101)the Clinical Specialized Discipline of Health System of Putuo District in Shanghai(No.2021tszk01).
文摘The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment(TIME).This study aimed to mechanistically assess whether Chang Wei Qing(CWQ)Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy.PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repairdeficient/microsatellite instability-high(dMMR/MSI-H)colorectal cancer(CRC),rather than those with mismatch repairproficient/microsatellite stable(pMMR/MSS)CRC.Hence,immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients.Flow cytometry was used to analyze T-lymphocytes in tumors from mice.Western blot was used to measure the expression of PD-L1 protein in mouse tumors.The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry.16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice.Subsequently,Spearman’s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes.The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins.In vivo,CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+and PD-1+CD8+T cells in tumors.Additionally,the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone.CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes,and Actinobacteria.Additionally,the proportion of infiltrated CD8+PD-1+,CD8+,and CD3+T cells were found to be positively correlated with the abundance of Akkermansia.Accordingly,CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.
