Citations

Introduction Uveal melanoma has a marked tropism for the liver where immune tolerance facilitates metastatic progression and resistance to immunotherapy. Impaired CD8 + T cell immunosurveillance is a central determinant of disease progression in uveal melanoma, yet the underlying mechanisms driving liver-mediated immune subpression and hepatic metastasis are not fully understood. Here, we investigate molecular pathways that regulated hepatic CD8 + T cell function and evaluate clinical outcomes associated with liver-directed therapy. Methods Expression of autotaxin (ATX), the expression responsible for generating lysophosphatidic acid (LPA), was evaluated in hepatic resident cell populations. ATX transcript levels were assessed in CD8 + T cells isolated from hepatic metastases and compared with matched peripheral blood and healthy donor control. Antigen-specific effector CD8 + T cells were used to characterize downstream signaling responses to LPA stimulation. Functional studies evaluating cytokine production during chronic antigen exposure were performed using CD8 + T cells from LPA receptor 5-deficient ( Lpar5 -/- ) mice. Results We identify the autotaxin-lysophosphatidic acid (ATX-LPA) axis as a prominent immunoregulatory pathway in the metastatic hepatic tumor microenvironment. ATX, the enzyme responsible for LPA production, is constitutively expressed by hepatic resident cells, is detectable on Kupffer cells and is associated with increased immunosubpressive markers. CD8 + T cells isolated from hepatic metastasis in a patient with uveal melanoma display markedly elevated ATX transcripts compared to matched peripheral blood (>5 log 2 fold change) and healthy controls. Using antigen-specific effector CD8 + T cells, we demonstrate LPA signaling induces low level, persistent ERK phosphorylation distinct from canonical antigen-induced TCR signaling. Genetic deletion of the LPA receptor 5 ( Lpar5 -/- ) on CD8 + T cells restores CD8 T cell percentages and cytokine function during persistent antigen stimulation in the presence of LPA. Discussion These findings define an ATX-LPA mechanisms of dysfunctional ERK signaling that may contribute to hepatic immune subpression in uveal melanoma. We highlight this pathway as a rational therapeutic target alongside liver-directed clinical interventions.

Objective: This study evaluated the surgical and long-term patient-reported quality of life outcomes of patients undergoing esophagectomy with gastric advancement. Methods: A retrospective review was performed of all patients undergoing esophagectomy with gastric advancement from 2005 to 2016. Quality of life outcomes were evaluated using the European Organization for research and treatment of cancer quality of life questionnaire - esophageal cancer module (QLQ-OES18), which covered 10 symptom scales: dysphagia, trouble swallowing saliva, choking when swallowing, eating, dry mouth, trouble with taste, trouble with coughing, trouble speaking, reflux, and pain. Results: A total of 129 patients were followed up to 16 years (791.3 patient-years). The median age was 63.5 (IQR 55.9-69.3) years, and 79.9% were male. Eighty-six percentage (111/129) of patients had esophageal malignancy as their operative indication. Median survival was 7.1 years, with patients with benign disease experiencing longer postoperative survival ( P = .006). The response rate to QLQ-OES18 surveys was 53.7% (22/41; median follow-up: 10.4 years). Patients who experienced early postoperative complications were more likely to report trouble with coughing ( P = .032) than those who did not experience early complications. However, postoperative leaks were not associated with worsened QOL. Of note, age ≥ 65 years, obesity status, surgical indication, location of the primary esophageal lesion, tumor stage, and the occurrence of delayed postoperative complications were not associated with long-term QOL (all P > .05). Conclusion: Patients undergoing esophagectomy with gastric advancement generally had good quality of life 10 years postoperatively, though early postoperative complications and gender appeared to influence symptom burden. These findings may improve pre and postoperative patient counseling.