Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment.

CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

Novel Prognostic Nomogram to Predict Progression-Free Survival of Patients with Hepatocellular Carcinoma After Transarterial Chemoembolization.

Purpose: A retrospective analysis of hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) to identify risk factors was conducted, and a novel predictive nomogram model was constructed. Patients and Methods: A total of 346 HCC patients who underwent TACE as initial treatment were retrospectively included, of which 208 were randomly allocated to the derivation cohort and 138 were allocated to the validation cohort. Progression-free survival (PFS) was used as the follow-up endpoint according to mRECIST. Kaplan‒Meier analysis and the Cox regression model screened out some indicators associated with short-term prognosis, and R language was further used to construct a nomogram model. The nomogram was compared with the classical BCLC staging system. Results: The independent predictors affecting PFS in HCC patients undergoing TACE included the following: 1. Baseline indicators: age (P=0.013), albumin-bilirubin (ALBI) grade (grade 2 vs grade 1, P=0.029; grade 3 vs grade 1, P<0.001), and portal vein tumour thrombus (PVTT, P<0.001); 2. Indicators at the 1-month follow-up: Neutrophil To Lymphocyte Ratio (NLR, P=0.032) and changes in alpha-fetoprotein (AFP, P<0.05) and des-γ-carboxy prothrombin (DCP, P<0.001); and 3. Cumulative treatment numbers of TACE in 6 months (P=0.007). In the derivation cohort, the calibration curve of the nomogram showed a high consistency between the predicted and actual PFS probability, and the nomogram outperformed the BCLC staging system (P=0.004). This result was also confirmed in the validation cohort (P=0.012). Conclusion: The constructed nomogram was suggested to have good predictive efficacy and could be used as a complementary assessment to predict the survival and prognosis of HCC patients treated with TACE.

Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis.

Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.

Clinical features and potential mechanism of coronavirus disease 2019-associated liver injury.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has posed a serious threat to global public health security. With the increase in the number of confirmed cases globally, the World Health Organization has declared the outbreak of COVID-19 an international public health emergency. Despite atypical pneumonia as the primary symptom, liver dysfunction has also been observed in many clinical cases and is associated with the mortality risk in patients with COVID-19, like severe acute respiratory syndrome and Middle East respiratory syndrome. Here we will provide a schematic overview of the clinical characteristics and the possible mechanisms of liver injury caused by severe acute respiratory syndrome coronavirus 2 infection, which may provide help for optimizing the management of liver injury and reducing mortality in COVID-19 patients.