PD‐1 and PD‐L1 upregulation promotes CD8<sup>+</sup> T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients

Shi, Feng; Shi, Ming; Zeng, Zhen; Qi, Ruizhao; Liu, Zhenwen; Zhang, Jiyuan; Yang, Yongping; Tien, Po; Wang, Fusheng

doi:10.1002/ijc.25397

Cited by 434 publications

(343 citation statements)

References 38 publications

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“…Similarly, Sawada et al showed that PD-1 is highly expressed on the CTLs of patients vaccinated with GPC3 [34]. PD-1/PD-L1 expression in tumor was significantly correlated with HCC stage, local recurrence rate and poor prognosis [35]. PD-1/PD-L1 expression in circulating cells was reported to correlate with the poor prognosis in HBV-positive HCC patients who underwent cryoablation [36].…”

Section: Pd-1mentioning

confidence: 90%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

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Section: Pd-1mentioning

confidence: 90%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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“…In addition, these neutrophils may also secrete agents that promote tumor cellular proliferation, angiogenesis, invasion and metastasis (46), and they may inhibit T cells (47). As important components of the non-specific and adaptive immune response, lymphocytes are able to destroy tumor cells via cytotoxic cells and cytokine secretion (48). A decreased lymphocyte count results in reduced tumor resistance (49).…”

Section: Discussionmentioning

confidence: 99%

C‑reactive protein/albumin and neutrophil/lymphocyte ratios and their combination predict overall survival in patients with gastric cancer

et al. 2017

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Abstract. Multiple studies have reported the prognostic association of certain inflammatory factors with various types of cancer. The present study assessed the prognostic value of the C-reactive protein (CRP)/albumin (Alb) ratio and the neutrophil/lymphocyte ratio (NLR), separately and in combination, in gastric cancer (GC). A total of 337 cases pathologically diagnosed with gastric adenocarcinoma were retrospectively evaluated. The clinicopathological and prognostic relevance of the CRP/Alb ratio and NLR and their combination were analyzed. The optimal cut-off values of the CRP/Alb ratio and NLR were 0.38 and 3.14, respectively. High CRP/Alb ratio (≥0.38) and NLR (≥3.14) values were associated with increased tumor invasion, more distant metastasis and a more advanced tumor-node-metastasis stage (all P<0.05). In addition, a high NLR value was also associated with increased tumor size (P= 0.02). The CRP/Alb ratio (≥0.38/<0.38) and NLR (≥3.14/<3.14) were independent prognostic factors for overall survival time (OS) in GC by multivariate analysis (P= 0.005 and P= 0.001). Using the CRP/Alb ratio and NLR classification, patients were stratified into three subgroups with different OS time (P<0.001), which were identified as independent prognostic variables in multivariate analysis (P<0.001). The present study demonstrated that the CRP/Alb ratio and NLR were independent prognostic factors for OS in patients with GC. The combination of these indexes was associated with significant prognostic value and may further stratify prognosis. IntroductionGastric cancer (GC) is one of the most common types of tumor globally. In 2015, GC had the second highest incidence and rate of mortality among cancer patients in China (1). Due to the rapid progression of GC and the absence of early specific symptoms and signs, the majority of patients are diagnosed at the late stage of gastric carcinoma (2-5). At present, surgery is the preferred treatment for patients without distant metastasis, and postoperative metastasis and recurrence are the predominant causes of mortality (3,5). Although disease-free and overall survival (OS) may be improved by postoperative chemotherapy and radiotherapy, the prognosis of GC remains poor (3,6). Identifying simple but effective prognostic markers for GC remains an important aim for researchers.Inflammation occurs in various types of tumor, and serves a crucial function in tumor development and distant metastasis (7-10). Previous studies have indicated that inflammation is associated with the formation of the tumor microenvironment by inflammatory mediators, including vasoactive amines and cytokines (11-13). The C-reactive protein (CRP)/albumin (Alb) ratio is used as a novel inflammation-based prognostic indicator in multiple types of tumor. Previous studies have demonstrated the prognostic value of CRP/Alb ratio in colorectal (14) and esophageal cancer (15), hepatocellular carcinoma (16), and renal (17) and pancreatic cancer (18). Another important inflammatory marker is the neutrophil/lymphocyte ratio (...

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“…13,18 This technique may have a renew interests in light of the expression of programmed cell death 1 (PD1) pathway in HCC and recent encouraging outcome demonstrated in patients treated with Nivolumab. 19,20 An international registry of clinical trials on CIK was established in 2010 by SchmidtWolf et al, with an aim to collect clinical data and standardize treatment of patients with cancer using CIK cells. 21 In previously published studies, CIK treatment has been shown to significantly improve patient survival, especially when combined with minimally invasive treatments to give a synergistic effect.…”

Section: Discussionmentioning

confidence: 99%

A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma

Xu¹,

Wang²,

Kim

et al. 2015

OncoImmunology

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Background & Aims: There is no generally accepted adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Autologous cytokine-induced killer (CIK) cells therapy has been reported to improve outcomes of patients with HCC, but its role as an adjuvant therapy remains unclear. This study aimed to evaluate the efficacy and safety of CIK as an adjuvant therapy for HCC after curative resection.Methods: This is a single center, phase 3, open label, randomized controlled trial (RCT). Two hundred patients who were initially diagnosed with HCC of Barcelona Clinic Liver Cancer (BCLC) stage A or B, and underwent curative hepatectomy were randomly assigned to receive four cycles of CIK treatment (the CIK group, n D 100) or no treatment (the control group, n D 100). The primary outcome was time to recurrence. The secondary outcomes included disease-free survival (DFS), overall survival (OS) and adverse events.Results: All patients in the CIK group finished the treatment by protocol. The median time to recurrence (TTR) was 13.6 (IQR 6.5-25.2) mo in the CIK group and 7.8 (IQR 2.7-17.0) mo in the control group (p D 0.01). There were no significant differences between the groups in DFS and OS. All adverse events were grade 1 or 2. There were no significant differences in incidence between the two groups.Conclusions: Four cycles of CIK therapy were safe and effective to prolong the median TTR in patients with HCC after curative resection, but the treatment did not improve the DFS and OS.

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PD‐1 and PD‐L1 upregulation promotes CD8⁺ T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients

Cited by 434 publications

References 38 publications

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

C‑reactive protein/albumin and neutrophil/lymphocyte ratios and their combination predict overall survival in patients with gastric cancer

A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma

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PD‐1 and PD‐L1 upregulation promotes CD8+ T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients

Cited by 434 publications

References 38 publications

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

C‑reactive protein/albumin and neutrophil/lymphocyte ratios and their combination predict overall survival in patients with gastric cancer

A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma

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PD‐1 and PD‐L1 upregulation promotes CD8⁺ T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients