| Background:Advanced biliary tract cancers(BTC)are aggressive malignancies with limited treatment options.Immunotherapy alone or combined with targeted therapy is far from satisfactory in BTC.Radiotherapy or local-regional therapy can enhance the efficacy of immunotherapy,but data in BTC is limited.The efficacy of immunotherapy is also influenced by the gut microbiome,but the distribution characteristics,metabolic features,and potential mechanisms in patients with BTC underwent immunotherapy are not clear.Methods:This study aims to assess the safety and efficacy of immunotherapy plus targeted therapy with local-regional therapy in BTC and explore the characteristics of the gut microbiota in patients with BTC underwent immunotherapy.In the first part,safety and efficacy of local-regional therapy,radiotherapy combined with PD-1 inhibitor and lenvatinib in advanced BTC will be explored through three cohort studies.In addition,the efficacy of direct or salvage radiotherapy on PD-1 inhibitor combined with lenvatinib will be further analyzed.In the second part,clinical data and fecal samples before and during treatment of advanced BTC patients receiving immunotherapy will be prospectively collected.The characteristics of the microbiome in different response groups and their related metabolic pathways will be analyzed through metagenomic sequencing.In the third part,significant differences in metabolites in different response group microbiomes were found through non-targeted metabolomic sequencing analysis,and potential metabolic pathways were explored.Correlation analyses of gut microbiota and metabolites were performed using Spearman’s correlation.Results:The first part of the cohort study found that local-regional therapy and radiotherapy can significantly enhance the efficacy of immunotherapy,with ORR of 32%35%and DCR of 85%-88%.The median overall survival time(mOS)of patients was 11.713.7 months,and the median progression-free survival time(mPFS)was 7.9-10.8 months.Direct or salvage radiotherapy can enhance the efficacy of immunotherapy,and the addition of radiotherapy or local-regional therapy did not cause new adverse reactions,and overall adverse reactions were controllable.In the second part,88 fecal samples of advanced BTC patients receiving immunotherapy were included.Metagenomic sequencing found that the abundance of Parabacteroides and GGB9615 was positively correlated with the response and prognosis,while Streptococcus and Bifidobacterium were negatively correlated.When both beneficial microbiota for survival were present,patients had a much better overall survival than those with only one or none.Dynamic analysis of the gut microbiota in the CBR group found that the composition of the gut microbiota tended to be stable,while the NCBR group showed a decreasing trend in species diversity.Pathway analysis showed that the CBR group was related to nucleotide metabolism,while the NCBR group was related to lipid metabolism.In the third part,54 fecal samples of advanced BTC patients receiving immunotherapy were included.Non-targeted metabolomic analysis found that there were 24 significantly different metabolites between different treatment response groups,and metabolites 4-[(hydroxymethyl)nitrosamino]-1(3-pyridyl)-1-butanone and pyrrolidine were related to the efficacy and survival,and these metabolites may be involved in immunotherapy through the pyrimidine metabolism pathway and tryptophan metabolism pathway.Correlation analysis of gut microbiota and metabolites found that the microbiota associated with better prognosis was related to the pyrimidine metabolism pathway,while the microbiota associated with poorer prognosis was related to the tryptophan metabolism pathway.Conclusion:Local-regional therapy and radiotherapy can enhance the efficacy of immunotherapy,and the efficacy of immunotherapy is also influenced by the richness of the gut microbiota,specific microbiota,and metabolites. |
PDF Full Text Request