Background and Aims: Selective Internal Radiation Therapy (SIRT) with Y90 microspheres is used to treat hepatocellular carcinoma (HCC) across tumor stages. Besides modulating the tumor microenvironment, SIRT may influence the immune response via a by-stander effect on immune cells that circulate through the tumor and non-tumor volume that absorbed radioactive beads. The NASIR trial has investigated the safety and efficacy of SIRT followed by nivolumab. This study investigates the peripheral immunological changes triggered by SIRT and their correlation with dosimetry parameters. Method: Blood samples were collected from 39 patients enrolled in the NASIR trial before SIRT (t1) and three weeks after the procedure (t2). Immunological profiling was conducted using multiparametric flow cytometry. Voxel-based dosimetry analysis in post-SIRT PET imaging included a) the highest mean absorbed dose (Dmean) among the treated nodules for each patient, and the total tumor volume exposed to at least 120 Gy (V120), and b) the Dmean, maximum absorbed dose, and non-tumor liver volume receiving at least 30 Gy (V30). Results: A significant reduction in total lymphocyte count was observed at t2 (-66.93%, CI 95% -68.71; -52.72; p< 0.0001), while other leukocyte populations remained unchanged. When subset populations were studied, a decline was observed in CD4, CD8, B, NK and NKT cells together with a marked increase in activated cells expressing programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3), and T cell immunoglobulin and mucin-domain containing-3 (TIM3), as well as functional markers like CD39 and PD-1 ligand (PDL1). These changes were noted across CD4 and CD8 T cells, regulatory T cells, myeloid-derived suppressor cells (MDSCs), monocytes, and dendritic cells. However, these alterations were in most cases not linked to the dose of radiation absorbed by the tumor or non-tumor liver volumes. Exceptions included significant correlations between the highest Dmean or V120 with CD4 T cells expressing CTLA-4 or LAG3. Additionally, increases in NK cells and dendritic cells were correlated with radiation exposure to the non-tumor liver, as measured by Dmean and V30 Conclusion: SIRT-induced lymphopenia suggests immune modulation. However, the increase in immune checkpoints and functional markers across various immune subsets indicates a potential antigen recognition response, associated to activation or exhaustion, and provides a rationale for combining Y90 with immune check-point inhibition beyond anti-PD1 antibodies. These findings highlight the complex relationship between radiation and immune modulation, suggesting that radiation dose may influence immune pathways
Peripheral immune cells changes after radioembolization (SIRT) in patients with hepatocellular carcinoma
PINTO, ELISA
2022/2023
Abstract
Background and Aims: Selective Internal Radiation Therapy (SIRT) with Y90 microspheres is used to treat hepatocellular carcinoma (HCC) across tumor stages. Besides modulating the tumor microenvironment, SIRT may influence the immune response via a by-stander effect on immune cells that circulate through the tumor and non-tumor volume that absorbed radioactive beads. The NASIR trial has investigated the safety and efficacy of SIRT followed by nivolumab. This study investigates the peripheral immunological changes triggered by SIRT and their correlation with dosimetry parameters. Method: Blood samples were collected from 39 patients enrolled in the NASIR trial before SIRT (t1) and three weeks after the procedure (t2). Immunological profiling was conducted using multiparametric flow cytometry. Voxel-based dosimetry analysis in post-SIRT PET imaging included a) the highest mean absorbed dose (Dmean) among the treated nodules for each patient, and the total tumor volume exposed to at least 120 Gy (V120), and b) the Dmean, maximum absorbed dose, and non-tumor liver volume receiving at least 30 Gy (V30). Results: A significant reduction in total lymphocyte count was observed at t2 (-66.93%, CI 95% -68.71; -52.72; p< 0.0001), while other leukocyte populations remained unchanged. When subset populations were studied, a decline was observed in CD4, CD8, B, NK and NKT cells together with a marked increase in activated cells expressing programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3), and T cell immunoglobulin and mucin-domain containing-3 (TIM3), as well as functional markers like CD39 and PD-1 ligand (PDL1). These changes were noted across CD4 and CD8 T cells, regulatory T cells, myeloid-derived suppressor cells (MDSCs), monocytes, and dendritic cells. However, these alterations were in most cases not linked to the dose of radiation absorbed by the tumor or non-tumor liver volumes. Exceptions included significant correlations between the highest Dmean or V120 with CD4 T cells expressing CTLA-4 or LAG3. Additionally, increases in NK cells and dendritic cells were correlated with radiation exposure to the non-tumor liver, as measured by Dmean and V30 Conclusion: SIRT-induced lymphopenia suggests immune modulation. However, the increase in immune checkpoints and functional markers across various immune subsets indicates a potential antigen recognition response, associated to activation or exhaustion, and provides a rationale for combining Y90 with immune check-point inhibition beyond anti-PD1 antibodies. These findings highlight the complex relationship between radiation and immune modulation, suggesting that radiation dose may influence immune pathways File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/81466