Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Abstract

The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios.

Selective Internal Radiotherapy Alters the Profiles of Systemic Extracellular Vesicles in Hepatocellular Carcinoma

“…Mice lacking CD40 were protected from alcohol-induced liver inflammation [46]. In a similar experimental setup, elevated levels of proinflammatory EVs were observed in the circulation of patients with cholangiocarcinoma (CCA) undergoing SIRT, which aligns with our findings [47]. Future studies should investigate whether there are variations between different tumor entities.…”

Advances in CAR T-cell therapy in bile duct, pancreatic, and gastric cancers

“…Bile duct cancer, pancreatic cancer, and gastric cancer are common digestive system tumors. Compared with other cancers, these digestive system tumors are prone to metastasis and have limited therapeutic effects from surgery, radiation, and chemotherapy ( 84 ). CAR T-cell therapy provides a more useful treatment for these types of cancers ( 43 , 57 , 69 ).…”

Recent Advances in Image-Guided Locoregional Therapies for Primary Liver Tumors

“…An investigation analyzing the peripheral blood of 114 patients with HCC showed a marked increase in programmed cell death protein 1, which was also associated with improved progno-sis [87]. A handful of investigations have also observed changes in immune responses to Y90 radioembolization for HCC and ICCA [88][89][90].…”