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Blocking immune checkpoint programmed cell death receptor 1 (PD-1) or programmed death receptor-ligand 1 (PD-L1) can enhance anti-tumor activity of effector T cells. However, the lack of response in many patients to PD-1/PD-L1 therapy remains a question. Improving the immunosuppressive tumor microenvironment (TME) to enhance the efficacy of immune checkpoint inhibitors has become a promising cancer treatment strategy. We constructed a liposome system (PD-L1/siCXCL12-Lp) of CXCL12 siRNA and anti-PD-L1 peptide with matrix metalloproteinases (MMPs) responsiveness, which combined the TME regulation of siCXCL12 and the immune regulation of anti-PD-L1 peptide. All animal experiments were approved by the Biomedical Ethics Committee of Peking University. The authors found that PD-L1/siCXCL12-Lp directly down-regulated the expression of CXCL12 in vitro (33.8%) and in vivo (15.5%). It also effectively increased the ratio of CD8+/Treg by 20.0%, which helped the anti-PD-L1 peptide to better exert its immune effect. The combination therapy significantly inhibited tumor growth (52.08%) with great safety, which explored a new idea for cancer immunotherapy.
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BACKGROUND@#The treatment mode of lung cancer is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for patients with EGFR mutant in non-small cell lung cancer (NSCLC). At the same time programmed death receptor 1 (PD-1) and its programmed death receptor ligand 1 (PD-L1) inhibitors therapy as the representative immune checkpoint inhibitors (ICIs) has a significant effect in the treatment of lung cancer. The aim of this study was to investigate the correlation between the expression of PD-1 and PD-L1 in NSCLC and clinicopathologic feature, EGFR gene mutation.@*METHODS@#The protein expression of PD-1 and PD-L1 was detected by immunohistochemistry from 127 patients with NSCLC and EGFR gene mutation was detected by quantitative polymerase chain reaction (qPCR) to analyze its relation with clinicopathologic feature. Also, the correlation between protein expression of PD-1 and PD-L1 and EGFR mutation.@*RESULTS@#The PD-1 positive expression in NSCLC tumor cells and tumor infiltrating immune cells is 53.5% (68/127), PD-L1 is 57.5% (73/127). The PD-1 and PD-L1 expression significantly higher in well-differentiated and moderately-differentiated carcinoma than poorly differentiated carcinoma, I+II than III+IV in clinical staging (P<0.05). The EGFR mutation rate was 46.5% (59/127), correlate with female, without smoking history, adenocarcinoma and well-differentiated and moderately-differentiated patients respectively higher than male, smoking history, squamous carcinoma and poorly differentiated patients (P<0.05). The protein expression of PD-L1 and PD-1 had the consistency in NSCLC patients (kappa=0.107,5, P=0.487). There was a negative correlation between the EGFR mutation and PD-1 and PD-L1 expression (Φ=-0.209, Φ=-0.221, P<0.05). Follow-up of NSCLC patients, the median total survival in under the age of 65, adenocarcinoma, well-differentiated and moderately-differentiated, with PD-L1 expression patients respectively higher than over the age of 65, squamous carcinoma, poorly differentiated, without PD-L1 expression patients (P<0.05). The median survival of hypo expression patients of PD-L1 significantly higher than hyper expression patient (P=0.04).@*CONCLUSIONS@#According to the Chinese Expert Consensus on Standards of PD-L1 immunohistochemistry testing for NSCLC, we tested the PD-L1 expression in NSCLC and then the dominant population of anti-PD-1/PD-L1 treatment was screened out. Patients with EGFR mutation were also detected and EGFR mutation was negatively correlated with the expression of PD-1 and PD-L1 as well. On the basis of PD-L1 expression and EGFR mutation status, it may benefit NSCLC patients from individualized treatment. Meanwhile, patients who were under the age of 65, adenocarcinoma, well-differentiated and moderately-differentiated, hypo expression of PD-L1 have a relatively good prognosis, to provide reference for the prognosis evaluation of NSCLC.
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@#Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor that seriously threatens human health and life. With increasing studies on the mechanism of tumor immune escape, programmed death receptor 1 (PD-1) and programmed death ligand receptor 1 (PD-L1) have been proven to be involved in tumor immune escape. The primary mechanism is that PD-1 recruits protein tyrosine phosphatase (SHP-2) to dephosphorylate downstream tyrosine kinase (SyK) and phosphatidylinositol 3-kinase (PI3K), thereby inhibiting downstream protein kinase B (AKT), extracellular regulated protein kinases (ERK) and other important signaling pathways, ultimately inhibiting T cell activation. In recent years, PD-1/PD-L1 inhibitors have become popular immunotherapies. Pembrolizumab and nivolumab have been approved for HNSCC patients by the U.S. Food and Drug Administration. Both durvalumab and atezolizumab are still in clinical trials, and published data show that both have certain safety and efficacy but still need much clinical data to support them. Meanwhile, the combination of PD-1/PD-L1 inhibitors with radiotherapy, chemotherapy and immunotherapy is still controversial in terms of clinical efficacy and adverse events, and further research is needed. However, serious immune-related adverse reactions limit the clinical application of PD-1/PD-L1 inhibitors, despite promising curative effects. Therefore, developing novel inhibitors and investigating stable and effective biomarkers and upstream and downstream signaling mechanisms are urgent issues.
ABSTRACT
The combination of programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) can inhibit and deplete T lymphocyte function, thereby inducing immune tolerance, enabling tumor cells to escape the attack of immune cells and promoting the growth and metastasis of tumors. At the same time, the high expression of PD-1/PD-L1 can enhance metastatic ability of tumors and lead to increased mortality, and the treatment of inhibiting PD-1/PD-L1 signaling pathway has been proved effective in many tumors. However, the traditional treatment methods are limited for the treatment of colorectal metastatic cancer. The emergence of immunotherapy may bring new breakthroughs for the treatment of colorectal metastatic cancer. This article reviews the characteristics of expressions of PD-1/PD-L1 in colorectal metastases.
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Programmed cell death-1 ( PD-1 ) is a member of the CD28/cytotoxic T lymphocyte-associated protein-4 (CTLA-4) family, expressed on activated T cells, B cells and macrophages.Programmed cell death-ligand 1 (PD-L1) can inhibit T cell proliferation , activation and cytokine secretion , and participate in the negative feedback regulation of T cell receptor signals.In a normal body, PD-1/PD-Ls signaling pathway plays an important role in maintaining immune tolerance,but can inhibit T cell immune response and promote tumor immune escape in case of tumor .The relationships between the expression and prognosis of PD-1/PD-L1 in soft tissue sarcoma ( STS ) and its biological significance , influencing factors of PD-1/PD-L1 expression , and research progress in related drugs and clinical applicability in STS are reviewed.
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Objective To investigate the relationship between programmed death receptor ligand 1 (PD-L1) and regulatory T cell(Treg) in non-small cell lung cancer.Methods Seventy-nine patients with non-small cell lung cancer who were treated in Hainan Provincial People's Hospital from December 2013 to December 2015 were selected.The levels of PD-L1 and Treg in cancer tissues and adjacent tissues were detected,observed the relationship with clinical pathological features,and analyzed the correlation of PD-L1 level and Treg infiltration.Results High expression of PD-L1 (53.2％,42/79) and Treg (50.6％,40/79) in cancer tissues were significantly higher than those in adjacent tissues (3.8％ (3/79),5.1％ (4/79)),the difference was significant (x2 =9.761,9.002,P＜0.05).High expression of PD-L1 (87.5％,28/32) and Treg(84.4％,27/32)were significantly higher in stage]Ⅲ and Ⅳ cancer tissues than those in stage Ⅰ and Ⅱ cancer tissues(29.8％(14/47),27.7％ (13/47)),the difference was significant (x2 =8.958,7.274,P ＜ 0.05).High expression of PD-L1 (85.3％,29/34) and Treg (88.2％,30/34) were significantly higher in lymph node metastasis cancer tissues than those in non-lymph node metastasis cancer tissues (28.9％ (13/45),22.2％ (10/45)),the difference was significant(x2=8.146,9.056,P＜0.05).The high level of PD-L1 in cancer tissues was positively correlated with high Treg infiltration (r =0.762,P＜0.05).Conclusion The expression of PD-L1 and Treg in non-small cell lung cancer tissues is related to the lymph node metastasis and stage,and the high expression of PD-L1 is positively correlated with the high infiltration of Treg.
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ObjectiveTo investigate the expression of programmed death receptor ligand 1 ( PD-L1 ) of peripheral blood mononuclear cells (PBMCs) in patients with hepatic cystic echincccccosis (HCE) and its relation with interferon-γ.MethodsThe clinical data of 63 patients with HCE who were admitted to the First Affiliated Hospital of Xinjiang Medical University from June 2010 to February 2011 were retrospectively analyzed.All patients were divided into HCE active group (38 patients) and HCE non-active group (25 patients) according to the system established by the World Health Organization's Informal Working Group on Echinocoecosis.Twenty patients with hepatic hemangioma or healthy individuals were recruited in normal control group.The positive rate of PD-L1 expression was detected by flow cytometry and immunocytochemistry.The expression of interferon-γ was detected by enzyme-linked immtmosorbent assay (ELISA).All data were analyzed by the t test,one-way analysis of variance,LSD test and chi-square test.The relationship between the expression of interferon-γ and positive rate of PD-L1 expression was analyzed by the Pearson test.ResultsThe results of flow cytometry showed that the positive rates of PD-L1 expression in the HCE active group,HCE non-active group and normal control group were 12.1％±3.8％,10.9％ ± 2.5％ and 9.1％ ±2.5％,respectively.There was a significant difference in the positive rate of PD-L1 expression between the HCE active group and normal control group (t =3.327,P ＜ 0.05 ).The results of immunohistochemistry showed that the positive rates of PD-LI expression in the HCE active group,HCE non-active group and normal control group were 11.9％ ± 3.4％,i0.6％ ± 2.9％ and 9.5％ ± 3.6％,respectively.There was a significant difference in the positive rate of PD-L1 expression between the HCE active group and normal control group (t =2.470,P ＜ 0.05 ).The expressions of intefferon-γ in the HCE active group,HCE non-active group and normal control group were ( 141 ± 38 ) μμg/L,( 124 ± 32 ) μg/L and ( 105 ± 42 ) μg/L.There wasasignificant difference in the expression of interferon-γ between the HCE active group and normal control group ( t =3.280,P ＜ 0.05).The results of flow cytometry and immunohistochemistry revealed that the positive rate of PD-L1 expression was positively correlated with the expression of interferon-γ( r =0.59,0.61,P ＜ 0.05 ).Conclusion With the help of interferon-γ,PD-L1 may play an important role in promoting the immune.evasion of echinococcus.