Differences between exhausted CD8⁺ T cells in hepatocellular carcinoma patients with and without uremia

The purpose of this study was to explore the differences between exhausted CD8⁺ T cells in hepatocellular carcinoma (HCC) patients with and without uremia. We enrolled 45 uremic patients who were recently diagnosed with HCC into the HCC + uremia cohort and similar patients with HCC but without uremia into the HCC-only cohort. Lymphocytes were obtained from the two cohorts, and exhausted CD8⁺ T cells, comprising PD-1⁺CD8⁺, TIM-3⁺CD8⁺, and LAG-3⁺CD8⁺ T cells, were sorted and expanded in vitro. After expansion, the proportions of PD-1⁺CD8⁺, TIM-3⁺CD8⁺, and LAG-3⁺CD8⁺ T cells were significantly higher in the HCC-only cohort than in the HCC + uremia cohort. CD8⁺ T cells expressing PD-1, TIM-3, or LAG-3 showed increased tumor reactivity and release of interferon-γ in vitro; however, these cells demonstrated weaker anti-tumor activity in HCC + uremia patients than in HCC-only patients. Among the expanded lymphocytes, only the decreased proportion of PD-1⁺CD8⁺ T cells significantly correlated with the HCC + uremia cohort (odds ratio of 2.731, p = 0.009). We concluded that peripheral CD8⁺ T cells expressing PD-1, TIM-3, or LAG-3 from the HCC + uremia cohort were dysfunctional in vitro. Among these populations, PD-1⁺CD8⁺ T cells were most evident in HCC patients with uremia.