Immune Modulation in Untreated, Contralateral Hepatic Metastases after Yttrium-90 Radioembolization of Microsatellite Stable Colorectal Cancer

Purpose: The study aimed to evaluate the immune response in untreated distant tumors following Y90-radioembolization for colorectal liver metastases (CRLM).

Material and Methods: Ten patients (nine male) with microsatellite-stable (MSS) CRLM with over five lesions were included. A baseline biopsy was performed before the Y90-radioembolization treatment of one liver lobe, followed by a second biopsy of yet untreated tumors in the other lobe directly before the second treatment (median interval between biopsies 13(4-49) days. Tumor biopsies and peripheral blood mononuclear cells (PBMCs) were analyzed for immune activity, including PD1, CD4, CD8, FoxP3, and CD68 in the tumor samples by multiplex immunophenotyping, while PBMCs were analyzed for quantification of lymphoid cell populations and expression of checkpoint molecules, including PD-1, TIGIT, CTLA-4, and TIM-3. Patients with an objective response or stable disease six months post-therapy were classified as “responders.”

Results: At baseline, biopsies of responders displayed lower FoxP3+cell and co-location of CD4+FoxP3+cell density compared to nonresponders (both p=0.02). At the second biopsy, nonresponders demonstrated higher CD68+macrophage density (p=0.0014). Responders exhibited fewer CD4+FoxP3+regulatory T cells than CD8+T cells at both time points (p=0.02 and p=0.0428). At the second biopsy, nonresponders tended to have an increased CD8+PD1+/CD8+ratio (p=0.062). Flow cytometry of nonresponders showed lower CD8+PD1+T cell density and CD8+PD1+/CD8+ratio at both timepoints.

Conclusion: Y90-radioembolization induces local immunogenic effects in untreated MSS CRLM lesions and systemic exhaustion of immune cells in nonresponders. The role of synergism of Y90-radioembolization and checkpoint inhibition warrants further investigation.

Publication History

Article published online:
20 January 2025