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

ABSTRACT

PURPOSE: To assess immunogenic effects in unembolized contralateral tumor after single lobar yttrium-90 transarterial radioembolization (90Y-TARE) of colorectal liver metastases (CRLMs). MATERIAL AND METHODS: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective AROMA trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial 90Y-TARE treatment of 1 liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 days (range, 4-49 days) immediately before second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMCs) were collected before treatments for immune cell analysis. Patients were stratified into responders and nonresponders based on tumor control or progression during follow-up. RESULTS: At baseline, responders (n = 4) displayed lower concentrations of FoxP3+ cells and colocation of CD4+FoxP3+ cells than nonresponders (both P = .02) in tumor tissues. At second biopsy, nonresponders showed a higher CD68+ macrophage density (P = .0014) than responders. Responders displayed fewer CD4+FoxP3+ T cells than CD8+ T cells at all time points (P = .02 and P = .0428). Nonresponders demonstrated a trending increase in CD68+ macrophages (P = .062), as well as a higher CD8+PD1+/CD8+ ratio (P = .062). PBMCs of nonresponders displayed lower CD8+PD1+ T cells and CD8+PD1+/CD8+ ratio at both time points. CONCLUSIONS: 90Y-TARE induces local immunogenic effects in nonexposed MSS CRLM, as well as systemic exhaustion of immune cells in nonresponders. Clinical implications such as a prognostic role or synergism of 90Y-TARE and checkpoint inhibition in MSS CRLM warrant further investigation.