Programmed death ligand 1 (PD-L1) expression represents a mechanism of immune escape by inhibiting T cell immunity. This study systematically evaluated the expression of PD-L1, spatial distribution of CD3 Moreover, type classification based on intratumoral CD3 infiltration and tumor cell PD-L1 expression was an independent prognostic factor for NPC patients. PD-L1 expression on tumor cells is a favorable prognosis factor in NPC patients with pre-existing intratumor-infiltrating lymphocytes.
Cytokine-induced killer (CIK) cell immunotherapy represents an effective treatment strategy for treating hepatocellular carcinoma (HCC). However, the therapeutic benefits of CIK cell treatment can be influenced by differences in complex immune microenvironment between patients. Herein, we investigated the relationship between PD-L1 expression and survival benefits of CIK cell immunotherapy in HCC patients. This retrospective study included 448 HCC patients: 217 cases underwent hepatectomy alone; 231 cases received hepatectomy and post-operative CIK cell transfusion. Immunohistochemistry was used to measure PD-L1 expression in tumor tissue sections from all patients. Meanwhile, flow cytometry was performed to explore the relationship between PD-L1 expression and localized inflammatory response in HCC microenvironment. We found a significantly improved prognosis in CIK treatment group compared with surgery alone group. In the CIK treatment group, higher PD-L1 expression was observed in patients who exhibited long-term survival benefit. Survival analysis showed patients with 5% PD-L1 expression had better overall survival (OS) and recurrence-free survival (RFS) than patients with 1-5% or <1% PD-L1 expression, particularly in the subgroup with high hepatitis B viral load. By contrast, PD-L1 expression did not show direct impact on the survival of patients in surgery alone group. Additionally, PD-L1 expression was found to be highly associated with hepatitis B viral load and the proportion of tumor-infiltrating lymphocytes in HCC patients. In conclusions, our study indicates that PD-L1 expression may reflect the presence of endogenous host immune response to tumor and serve as a biomarker for predicting survival benefits from adjuvant CIK cell immunotherapy in HCC patients.
To examine the relationship between cytotoxic T lymphocyte antigen-4 (CTLA-4) expression and esophageal carcinoma prognosis, CTLA-4 expression was immunohistochemically detected in paraffin-embedded primary tumor specimens from 158 patients with esophageal cancer. CTLA-4 was detected in the cytoplasm and cell membranes of esophageal cancer cells and in interstitial lymphocytes. In univariate analyses (log-rank), higher interstitial CTLA-4+ lymphocyte density and higher tumor CTLA-4 expression were associated with shorter overall survival (OS). After controlling for age and clinical stage, multivariate analysis (Cox) found that tumor CTLA-4 expression was an independent predictor of shorter OS (HR 2.016, P = 0.004). These results indicate that CTLA-4 expression in the tumor environment (both lymphocytes and tumor cells) is associated with poorer prognosis. In addition, CTLA-4 profiles may be useful for predicting the benefits and toxicity of CTLA-4 blockade in patients with esophageal carcinoma.
Protein kinase CK2 alpha (CK2α), one isoform of the catalytic subunit of serine/threonine kinase CK2, has been indicated to participate in tumorigenesis of various malignancies. We conducted this study to investigate the biological significances of CK2α expression in hepatocellular carcinoma (HCC) development. Real-time quantitative polymerase and western blotting analyses revealed that CK2α expression was significantly increased at mRNA and protein levels in HCC tissues. Immunohistochemical analyses indicated that amplified expression of CK2α was highly correlated with poor prognosis. And functional analyses (cell proliferation and colony formation assays, cell migration and invasion assays, cell cycle and apoptosis assays) found that CK2α promoted cell proliferation, colony formation, migration and invasion, as well as inhibited apoptosis in hepatoma cell lines in vitro. CK2α-silenced resulted in significant apoptosis in cells that was demonstrated been associated with downregulation of expression of Bcl-2, p-AKT (ser473) and upregulation of expression of total P53, p-P53, Bax, caspase3 and cleaved-caspase3 in HCC cells. In addition, experiments with a mouse model revealed that the stimulative effect of CK2α on tumorigenesis in nude mice. Our results suggest that CK2α might play an oncogenic role in HCC, and therefore it could serve as a biomarker for prognostic and therapeutic applications in HCC.
Cytokine-induced killer (CIK) cells that are stimulated using mature dendritic cells (DCs), referred to as (DC-CIK cells) exhibit superior anti-tumor potency. Anti-programmed death-1 (PD-1) antibodies reinvigorate T cell-mediated antitumor immunity. This phase I study aimed to assess the safety and clinical activity of immunotherapy with PD-1 blockade (pembrolizumab)-activated autologous DC-CIK cells in patients with advanced solid tumors. Patients with selected types of advanced solid tumors received a single intravenous infusion of activated autologous DC-CIK cells weekly for the first month and every 2 weeks thereafter. The primary end points were safety and adverse event (AE) profiles. Antitumor responses, overall survival (OS), progression-free survival (PFS) and cytolytic activity were secondary end points. Treatment-related AEs occurred in 20/31 patients. Grade 3 or 4 toxicities, including fever and chills, were observed in two patients. All treatment-related AEs were reversible or controllable. The cytotoxicity of DC-CIK cells induced up-regulation of PD-L1 expression on autologous tumor cells. When activated using pembrolizumab , DC-CIK cells exerted superior antitumor properties and elevated IFN-γ secretion. Objective responses (complete or partial responses) were observed in 7 of the 31patients.These responses were durable, with 6 of 7 responses lasting more than 5 months. The overall disease control rate in the patients was 64.5%. At the time of this report, the median OS and PFS were 270 and 162 days, respectively. In conclusions, treatment with pembrolizumab-activated autologous DC-CIK cells was safe and exerted encouraging antitumor activity in advanced solid tumors. A larger phase II trial is warranted.
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