In this study, a comprehensive analysis was conducted on the clinical data of 75 patients diagnosed with ICC who underwent immunotherapy. COX regression analysis was employed to identify independent prognostic factors, including CA19-9, albumin levels, presence of other site metastases, PVTT grade, administration of bifidobacteria, surgical intervention, radiotherapy, combined peritoneal effusion, treatment-related adverse events, and Child-Pugh stage. These factors were incorporated into nomogram models to evaluate their significance and provide valuable insights for clinical diagnosis and treatment decision-making in the field.
Several ICIs have demonstrated potent and durable antitumor activity and have been approved by the FDA for the treatment of various malignancies21-23. Immunotherapy has shown enhanced efficacy in viral infection-associated tumors, including head and neck cancer, Hodgkin lymphoma, and HCC, owing to the presence of neoantigens associated with viral infections24-26. However, despite the association of ICC with chronic infections such as hepatic schistosomiasis, viral hepatitis B and C, and bacterial septic cholangitis27, there is currently no evidence supporting the significant benefit of immunotherapy monotherapy in ICC. Recent studies have increasingly demonstrated that combining immunotherapy with other treatment regimens can lead to prolonged survival and substantial clinical benefits for patients14,28-31.
While immunotherapy is generally considered safe, a subset of patients may encounter severe immune-related adverse events, particularly when combined with other therapies32. Therefore, there is a pressing need for reliable immunotherapy biomarkers that can effectively identify individuals who would benefit from such treatment. Currently recognized biomarkers include tumor mutational burden (TMB) 33, microsatellite instability-high (MSI-H) status34, and programmed cell death ligand 1 (PD-L1) expression. However, these markers possess certain limitations and do not provide an entirely accurate prediction of patient prognosis21. With the increasing utilization of immunotherapy, there is an urgent demand for more precise biomarkers that can reliably forecast patient outcomes.
Nomograms are widely utilized in various tumor prognostic models and have demonstrated the ability to enhance predictive accuracy35-37. In this study, we constructed and validated a prognostic nomogram for ICC by incorporating independent risk factors derived from Cox regression analysis. This nomogram allowed us to effectively identify patients who would benefit from treatment during follow-up. Moreover, we developed two separate line graphs to predict OS and PFS in patients undergoing immunotherapy, and subsequently validated these predictions. Our findings confirmed that baseline CA19-9 levels, cancer embolism grade, bifidobacteria administration, and surgical intervention were significant factors that collectively influenced the OS prediction for immunotherapy in cholangiocarcinoma patients. Additionally, CA19-9 levels, albumin levels, and bilirubin levels were influential factors that jointly predicted PFS.
The role of microbes in the development, diagnosis, and treatment of cancer has been a subject of ongoing debate and investigation within the scientific community. Alterations in the gut microbiota have been shown to modulate the immune response38. Bacterial outer membrane vesicles (OMVs) have been found to possess the ability to inhibit tumor growth and metastasis through interferon-gamma mediated anti-tumor responses39. Studies by Noriho Iida et al. have indicated that cancer-bearing mice treated with antibiotics or maintained under sterile conditions exhibited poor responses to therapeutic interventions, suggesting that an integrated symbiotic microbiota is necessary to modulate the tumor microenvironment for effective anti-tumor therapy39,40. Lijuan Wang et al. reported that certain gut microflora can induce TNF-α production while down-regulating PD-L1 expression41. Lukas F Mager et al. demonstrated that specific bacteria, including Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species, significantly enhanced the efficacy of ICIs, further supporting the notion that microorganisms can potentiate immunotherapy42. In our study, a subset of patients had been consuming oral bifidobacteria for an extended duration to regulate their gut flora. The final results confirmed that these patients indeed exhibited a significant advantage in terms of OS. However, there are no existing studies that specifically address the underlying reasons for this phenomenon. We intend to continue collecting relevant data and conducting mechanistic studies to further elucidate the mechanisms involved.
In conclusion, the nomogram developed in this study demonstrates a high level of accuracy in predicting the prognosis of immunotherapy in ICC patients. Additionally, our findings provide novel evidence suggesting that oral bifidobacteria supplementation can significantly extend OS in these patients. Nonetheless, it should be noted that the low incidence of ICC and the limited sample size in this study necessitate further validation of the nomogram's predictive capacity. Future research endeavors will include the inclusion of a larger patient cohort to ensure robustness and generalizability of the findings.