Immune infiltrates in metastatic uveal melanoma liver metastases and associations with clinical outcomes.
Authors: Smith Katherine Emilie Rhoades , Jenkins Sarah M. , Dimou Anastasios , Dudek Arkadiusz Z. , Block Matthew Stephen , Markovic Svetomir , McWilliams Robert R. , Kottschade Lisa A. , Montane Heather N , Salomao Diva , Javed Asad 
Published: June 2023

9538

Background: Uveal melanoma has a poor prognosis following metastasis to the liver. Immune checkpoint inhibitors (ICIs) are often utilized in patients with metastatic uveal melanoma (MUM); however, ICIs in MUM have low response rates. We studied the association of immune infiltrates in MUM liver metastases with survival outcomes for all patients, in addition to evaluating if immune infiltrates improve survival for patients treated with ICIs. Methods: We included MUM patients with liver metastases who had pre-treatment liver biopsies available at Mayo Clinic Rochester. Demographics, disease characteristics, treatments, and clinical outcomes were obtained from the electronic medical record. Core biopsies of liver metastases were reviewed for the presence of lymphocytes at interface of the tumor and liver parenchyma, and for tumor-infiltrating lymphocytes (TILs). If TILs were present, then additional immunohistochemistry (IHC) staining was performed for CD3, CD4, CD8, PD1, CD25, and FoxP3. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with Cox proportional hazards regression. Median OS and hazard ratios (HR) were calculated and p-values (p) <0.05 were considered statistically significant. Results: 140 patients with MUM who had pre-treatment liver biopsies were identified. 122 biopsies were evaluable for the presence of lymphocytes, either at the tumor-liver interface, or for TILs. 80/122 (65.6%) biopsies showed presence of any lymphocyte and 27/80 had TILs. 27 biopsies had sufficient tissue for further IHC classification. CD8+ T cells were identified in 27/27 samples, T cell PD1 positivity ≥1% in 4/27 samples, and regulatory T cell markers (CD25 and/or FoxP3) in 18/27 samples. Median OS for the entire cohort was 16 months (mo). Patients still alive at the time of data analysis had at least one year of follow-up available (range 13-124 mo). Univariate analyses (UVA) showed no significant improvement in OS based on the presence of any lymphocytes (HR 1.01, p 0.98), lymphocytes at the tumor-liver interface (HR 1.10, p 0.64), TILs (HR 0.78, p 0.27), >50% CD8+ T cells (HR 0.88, p 0.77), or absence of FoxP3+ T cells (HR 0.68, p 0.40). In the 69 patients treated with ICIs (pembrolizumab, nivolumab, or ipilimumab plus nivolumab), neither the presence of any lymphocytes (HR 1.19, p 0.56) nor TILs (HR 0.68, p 0.24) were associated with an OS benefit. Conclusions: We present a large cohort of patients with MUM where we characterized immune infiltrates in liver metastases and evaluated clinical outcomes. OS did not significantly improve with the presence of any lymphocytes, TILs, CD8+ T cells, or with the absence of FoxP3+ T cells. These results were consistent across all patients whether they were treated with ICIs or not. Our findings suggest that lymphocytes in MUM are functionally dormant and highlights the need for novel immune-activating treatment strategies.