Immune modulation in untreated, contralateral hepatic metastases after Y90-radioembolization of microsatellite stable (MSS) colorectal cancer.

ABSTRACT

PURPOSE: To assess immunogenic effects in unembolized contralateral tumor after single lobar Y90-radioembolization (SIRT) of colorectal liver metastases(CRLM). MATERIAL AND METHODS: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective BLINDED trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial SIRT treatment of one liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 (4-49) days immediately prior to second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMC) were collected before treatments for immune cell analysis. Patients were stratified into "responders" and "non-responders" based on tumor control or progression during follow up. RESULTS: At baseline, responders (n=4) displayed lower concentrations of FoxP3+ cells and co-location of CD4+FoxP3+ cells than non-responders (both p=0.02) in tumor tissues. At second biopsy, non-responders showed a higher CD68+ macrophage density (p=0.0014) than responders. Responders displayed fewer CD4+FoxP3+ T cells than CD8+ T cells at all timepoints (p=0.02 and p=0.0428). Non-responders demonstrated a trending increase of CD68+ macrophages (p=0.062), as well as a higher CD8+PD1+/CD8+ ratio (p=0.062). PBMC of non-responders displayed lower CD8+PD1+ T cells and CD8+PD1+/CD8+ ratio at both timepoints. CONCLUSION: SIRT induces local immunogenic effects in non-exposed MCC CRLM, as well as systemic exhaustion of immune cells in non-responders. Clinical implications such as a prognostic role or synergism of SIRT and checkpoint inhibition in MSS CRLM warrant further investigation.