Research progress of MSI-CRC on anti-PD-1 therapy / 国际外科学杂志

The programmed cell death receptor 1 (PD-1) antibody has been used in the treatment of a variety of malignant tumors, in which colorectal cancer is considered immune " cold" tumor and is not sensitive to anti-PD-1 therapy. The molecular characteristics of mismatch repair deficient (dMMR)/high microsatellite instability (MSI-H) are important molecular markers for screening patients with immune checkpoint inhibitors therapy (ICIs). However, only some patients can benefit from ICIs treatment, and some patients even have disease progression. This article summarizes the research progress of anti-PD-1 immunotherapy of MSI-CRC in recent years, including the mechanisms of resistance, new efficacy biomarkers and treatment options, so as to provide ideas for expanding the application of immunotherapy in colorectal cancer.

Expression of PD-1/PD-L1 in esophageal squamous cell carcinoma and its relationship with survival prognosis: A systematic review and meta-analysis / 中国胸心血管外科临床杂志

@# Objective    To systematically evaluate the expression of programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in esophageal squamous cell carcinoma and its relationship with prognosis. Methods    The literature from PubMed, EMbase, The Cochrane Library, Web of Science, CNKI and Wanfang data from inception to February 22, 2020 was searched by computer. Data were extracted and the quality of literature was evaluated using RevMan 5.3 software for meta-analysis. Egger's and Begg's tests were used to evaluate publication bias, and Stata 15.1 software was used for sensitivity analysis. Results     A total of 16 articles were included, and there were 3 378 patients with esophageal squamous cell carcinoma. The methodological index for nonrandomized studies (MINORS) scores were all 12 points and above. The meta-analysis results showed that the positive expression rates of PD-1 and PD-L1 in tumor cells were 37.8% (190/504) and 41.7% (1 407/3 378), respectively. The positive expression of PD-L1 in tumor immune infiltrating cells was 41.7% (412/987). The overall survival (OS) of the tumor cell with high PD-L1 expression was lower than that with low PD-LI expression (HR=1.30, 95%CI 1.01-1.69, P=0.04). The OS of the tumor immune infiltrating cell with high PD-L1 expression was significantly higher than that with low PD-LI expression (HR=0.65, 95%CI 0.53-0.80, P<0.000 1). Conclusion    PD-L1 has a high expression rate in esophageal squamous cell carcinoma and is an important factor for the prognosis of esophageal squamous cell carcinoma.

Research Progress on the Mechanism and Clinical Data of Cereblon in Reversing the Resistance of Lung Cancer to PD-1 Antibody by T cells / 中国肺癌杂志

Programmed cell death receptor 1 (PD-1) is a membrance-spanning protein mostly expressed in the T cell, and combines with programmed cell death ligand 1 (PD-L1) in the targeting cell. When binding to the ligand on tumor cells, PD-1 as an immunosuppressive molecule, can inhibit the immune function of T cells, thus tumor immune escape. For example, depletion of peripheral effector T cell and accelerate the transformation of effector T cells into regulator T cells. To solve this problem, PD-1 antibody is used to bind to PD-1 on T cells to inhibit the interaction between PD-1 on the T cells and PD-L1 on the tumor cells so that it can restore the function of T cells to kill tumor cell. PD-1 antibodies, such as Nivolumab and Pembrolizumb, are approved as a first-line treatment for advanced non-small cell lung cell cancer. However, due to the interaction of tumor cells, T cells and cytokines, some patients developed drug resistance which reduces the efficacy of immunotherapy. Hence, how to overcome resistance has become a urgent problem. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex and the only known molecular receptor of immunoregulatory drugs, has been found to reverse PD-1 antibody resistance by binding to CRBN regulatory agents (CMS), exert T cell immune function by regulating proliferation, activation and metabolism of T cell. In this paper, the mechanism of down-regulation of T cells leading to resistance of PD-1 antibody in lung cancer, the mechanism of CRBN regulating T cells, and research progress of CRBN regulator in the treatment of lung cancer were reviewed.
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Identifying protein epitopes recognized by monoclonal antibodies / 生物工程学报

To establish a method for identifying protein epitopes recognized by therapeutic monoclonal antibodies, the programmed death receptor-1 (PD-1) was selected as the target protein. Based on the alanine scanning strategy, a rapid expression method of antigen mutants combining site-directed mutagenesis with mammalian cell expression system was established, the conditions for eukaryotic expression element amplification and cell transfection expression were established. 150 PD-1 protein mutants were co-expressed, and the binding ability of these mutants to anti-PD-1 antibody Pembrolizumab was identified. The epitopes of Pembrolizumab were determined based on the binding ability of protein mutants to antibodies and combined with protein structure analysis, which was highly consistent with the reported crystal structure-based epitopes, indicating that this method is simple and accurate and can be used for epitope mapping of therapeutic monoclonal antibodies.

Lichen Planus Developed During the Treatment with Nivolumab in a Patient with Lung Cancer: A Case Report and Literature Review / 대한피부과학회지

Nivolumab is a fully-humanized IgG4 monoclonal antibody that competitively binds to the programmed cell death receptor-1 protein (an immune check-point molecule) present on activated T cells. Nivolumab is approved for the treatment of advanced melanoma, lung cancer, and renal cell carcinoma. It attenuates the inactivation of cytotoxic CD8+ T cells and, produces an antitumor effect; however it may be associated with immune-related adverse events, including the development of lichen planus (LP). A 72-year-old man presented with a 2-month history of multiple, polygonal, purplish papules on the dorsal aspect of both hands. He was diagnosed with large cell neuroendocrine carcinoma (LCNEC) of the lung 4 years earlier and was treated with nivolumab (3 mg/kg every 2 weeks) for 9 months. By the 14th course of nivolumab therapy, the patient developed multiple rashes on the dorsal aspect of both hands, and biopsy was consistent with findings of LP. We report a rare case of LP in a patient with lung cancer treated with nivolumab.

Cancer Immunotherapy Related Endocrine Adverse Effects

Cancer immunotherapy has emerged as a promising therapy for a wide variety of tumors. Immune checkpoint inhibitors including anti cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) monoclonal antibodies have proven to be especially effective in various advanced cancers. However, cancer the immunotherapy disturbs the immune system and may also cause immune related side effects (IRAE) distinguished from cytotoxic chemotherapy toxicity. Among them, endocrine IRAE has been reported with a higher incidence than other organ IRAE. We focus on the most relevant and new aspects related to endocrine IRAE due to cancer immunotherapy in this review.

Role of programmed cell death receptor 1 signaling pathway in cancer immunotherapy / 基础医学与临床

Research in immunotherapy has achieved important progress in tumor treatment. Programmed cell death receptor 1(PD-1) is mainly expressed on the T lymphocyte surface and serves as an important immune regu-lator. The interactions of PD-1 and its ligand, PD-L1 are involved in tumor-induced immunosuppression. Some of the approved antibody preparations targeting PD-1/PD-L1 signaling showed significant clinical benefits.

Association between high expression of intrahepatic programmed death-1 and liver inflammation in patients with autoimmune hepatitis / 中华肝脏病杂志

Objective@#To investigate the expression of programmed death-1 (PD-1) in liver tissue and its association with liver pathology in patients with autoimmune hepatitis (AIH).@*Methods@#A total of 54 AIH patients (38 in the active stage and 16 in the remission stage) were enrolled, and 9 healthy volunteers were enrolled as control group. Immunohistochemistry combined with quantitative image analysis was used to measure the expression of PD-1 in liver tissue. The t-test, rank sum test, one-way analysis of variance, least significant difference t-test, Mann-Whitney U test, and Pearson relation analysis were used for statistical analysis of different types of data.@*Results@#The AIH group had a significantly higher positive rate of PD-1 in liver tissue than the control group (13.57%±6.84% vs 2.22%±0.66%, P < 0.01), and the patients in the active stage of AIH had a significantly higher positive rate of PD-1 in liver tissue than those in the remission stage (16.53%±7.72% vs 6.56%±3.16%, P < 0.01). The positive rate of PD-1 in liver tissue was 6.56%±3.16% in G0 group, 14.33%±5.08% in G1-2 group, and 19.23%±5.41% in G3-4 group (P < 0.01), but there was no significant difference in the positive rate of PD-1 between S0, S1-2, and S3-4 groups (P > 0.05). In AIH patients, the positive rate of PD-1 in liver tissue was positively correlated with the levels of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and IgG (r = 0.665, 0.721, 0.711, and 0.813, all P < 0.01).@*Conclusion@#AIH patients have regulated PD-1 expression in liver tissue, which is closely associated with liver inflammation and is not associated with fibrosis degree, suggesting that PD-1 is involved in the development and progression of inflammation in AIH patients.