• Molecules and Cells
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• 제44권5호
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• pp.363-373
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• 2021

Immune checkpoint inhibitors have changed the paradigm of treatment options for non-small cell lung cancer (NSCLC). Monoclonal antibodies targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have gained wide attention for their application, which has been shown to result in prolonged survival. Nevertheless, only a limited subset of patients show partial or complete response to PD-1 therapy, and patients who show a response eventually develop resistance to immunotherapy. This article aims to provide an overview of the mechanisms of acquired resistance to anti-PD-1/PD-L1 therapy from the perspective of tumor cells and the surrounding microenvironment. In addition, we address the potential therapeutic targets and ongoing clinical trials, focusing mainly on NSCLC.

• Journal of Yeungnam Medical Science
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• 제38권4호
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• pp.308-317
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• 2021

Cancer is the leading cause of death and is on the rise worldwide. Until 2010, the development of targeted treatment was mainly focused on the growth mechanisms of cancer. Since then, drugs with mechanisms related to tumor immunity, especially immune checkpoint inhibitors, have proven effective, and most pharmaceutical companies are striving to develop related drugs. Programmed cell death-1 and programmed cell death ligand-1 inhibitors have shown great success in various cancer types. They showed durable and sustainable responses and were approved by the U.S. Food and Drug Administration. However, the response to inhibitors showed low percentages of cancer patients; 15% to 20%. Therefore, combination strategies with immunotherapy and conventional treatments were used to overcome the low response rate. Studies on combination therapy have typically reported improvements in the response rate and efficacy in several cancers, including non-small cell lung cancer, small cell lung cancer, breast cancer, and urogenital cancers. The combination of chemotherapy or targeted agents with immunotherapy is one of the leading pathways for cancer treatment.

• Journal of Veterinary Science
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• 제22권5호
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• pp.75.1-75.10
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• 2021

Background: Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have important roles in tumor evasion of the immune system. Objectives: This study aimed to assess the diagnostic utility of circulating PD-1 and PD-L1 levels in healthy dogs and dogs with tumors. Methods: Circulating PD-1 and PD-L1 levels in the serum of 71 dogs with tumors were compared with those of 52 healthy dogs by performing enzyme-linked immunosorbent assay (ELISA). Results: The ELISA results revealed higher circulating PD-1 and PD-L1 levels in dogs with tumors (2.9 [2.2-3.7] ng/mL; median [IQR] and 2.4 [1.4-4.4] ng/mL, respectively) than in healthy dogs (2.4 [1.9-3.0] ng/mL; p = 0.012 and 1.4 [0.9-2.1] ng/mL; p < 0.001, respectively). Especially, there was a significant difference in circulating PD-1 levels between healthy dogs and dogs with malignant epithelial tumors (2.4 [1.9-3.0] ng/mL and 3.1 [2.6-4.4] ng/mL, respectively; p < 0.01). In addition, there was a significant difference in circulating PD-L1 levels between healthy dogs and dogs with lymphomas (1.4 [0.9-2.1] ng/mL and 2.7 [1.6-5.8] ng/mL, respectively; p < 0.001). Conclusion: This study indicates that circulating PD-1 and PD-L1 have potential as tumor diagnostic biomarkers in dogs with tumors.

• BMB Reports
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• 제54권1호
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• pp.12-20
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• 2021

In the last decade, we have witnessed an unprecedented clinical success in cancer immunotherapies targeting the programmed cell-death ligand 1 (PD-L1) and programmed cell-death 1 (PD-1) pathway. Besides the fact that PD-L1 plays a key role in immune regulation in tumor microenvironment, recently a plethora of reports has suggested a new perspective of non-immunological functions of PD-L1 in the regulation of cancer intrinsic activities including mesenchymal transition, glucose and lipid metabolism, stemness, and autophagy. Here we review the current understanding on the regulation of expression and intrinsic protumoral activity of cancer-intrinsic PD-L1.

• Tuberculosis and Respiratory Diseases
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• 제65권4호
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• pp.343-350
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• 2008

PD-L1 is expressed in a variety of antigen-presenting cells and provides T cell tolerance via ligation with its receptor PD-1 and B7-1 on T cells. Stimulation with lipopolysaccharide (LPS) can increase the level of PD-L1 expression in B cells and macrophages, which suggests that this molecule plays a role in the immunosuppression observed in severe sepsis. The aim of this study was to identify which of the downstream pathways of TLR4 are involved in the up-regulation of PD-L1 by LPS in macrophages. Flow cytometry was used to examine the expression of PD-L1 in RAW 264.7 macrophages stimulated with LPS. The following chemical inhibitors were used to evaluate the role of each pathway: LY294002 for PI3K/Akt, SB202190 for p38 MAPK, and U0126 for MEK. LPS induced the expression of PD-L1 in a time- and dose-dependent manner. Transfection of siRNA for TLR4 suppressed the induction of PD-L1. Pretreatment with LY294002 and SB202190 decreased the level of PD-L1 expression but U0126 did not. Overall, the PI3K/Akt and p38 MAPK pathways are involved in the up-regulation of PD-L1 expression in RAW 264.7 macrophages stimulated with LPS.

• Radiation Oncology Journal
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• 제34권4호
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• pp.250-259
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• 2016

Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.

• 미생물학회지
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• 제49권4호
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• pp.301-308
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• 2013

Programmed Death-1 (PD-1)은 중요한 면역조절분자들 중 하나로 다양한 면역활성인자에 자극된 T 세포, B 세포, NKT 세포 및 대식세포에서 발현된다. Lipopolysaccaride (LPS)는 그람음성세균의 세포벽구성물질로 PD-1 발현을 유도하는 중요 면역원들 중 하나로 알려져 있다. 그러나 선천면역세포에서 PD-1 발현기전에 관한 연구는 미비한 실정이다. 본 연구에서는 LPS에 의해 자극된 Raw264.7 세포주를 대상으로 PD-1 발현 및 발현조전기전을 RT-PCR, Western Blot, 유세포분석기, ChIP assay 및 co-immunoprecipitation 방법으로 조사하였다. Raw264.7 세포주가 LPS로 자극되었을 때 PI3K 및 p38 신호전달경로를 경유하여 PD-1 발현이 크게 증가되었다. 또한 LPS 주사된 생쥐의 비장유래 대식세포에서도 PD-1 발현이 증가됨을 확인 하였다. PD-1 유전자의 프로모터 분석을 통해서 NF-${\kappa}B$ 및 IRF-1 결합부위가 PD-1 발현에 중요함을 알 수 있었다. 또한 PD-1 발현을 극대화하기 위하여 전사조절인자 NF-${\kappa}B$ 및 IRF-1의 공동활성이 필수적임을 확인하였다. 본 연구결과는 LPS 유도 생쥐패혈증모델에서 선천면역세포에 발현된 PD-1분자의 제어를 통한 질병 연구에 유용한 자료로 이용될 수 있을 것으로 사료된다.

• 대한영상의학회지
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• 제85권2호
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• pp.394-408
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• 2024

목적 CT 영상 소견을 이용하여 편평세포폐암에서 programmed death ligand 1 (이하 PD-L1)의 발현을 예측하는 모델을 구축해 보고자 하였다. 대상과 방법 PD-L1 발현검사 결과를 포함하고 있는 97명의 편평세포폐암 환자를 포함하였고 종양 치료 전 시행한 CT 영상 소견을 분석하였다. 전체 환자군과 40명의 진행성(≥ stage IIIB) 병기 환자군에 대하여 PD-L1 발현 예측을 위한 다중 로지스틱 회귀 분석 모델 구축을 시행하였다. 각각의 환자군에 대하여 곡선 아래 면적(areas under the receiver operating characteristic curves; 이하 AUCs)을 분석하여 예측력을 평가하였다. 결과 전체 환자군에서 '전체 유의인자 모델'(종양병기, 종양크기, 흉막결절, 폐전이)의 AUC 값은 0.652이며, '선택 유의인자 모델'(흉막결절)은 0.556이었다. 진행성 병기 환자군에서 '선택 유의인자 모델'(종양크기, 흉막결절, 폐소수전이, 간질성폐렴의 부재)의 AUC 값은 0.897이었다. 이러한 인자들 중 흉막결절과 폐소수전이는 높은 오즈비를 보였다(각각, 8.78과 16.35). 결론 본 연구에서의 모델은 편평세포폐암의 PD-L1 발현예측의 가능성을 보여주었으며 흉막결절과 폐소수전이는 PD-L1 발현을 예측하는데 중요한 CT 예측인자였다.

• 미생물학회지
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• 제49권3호
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• pp.221-227
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• 2013

인간면역결핍바이러스(Human immunodeficiency virus; HIV), B형 간염 바이러스(Hepatitis B virus; HBV), 그리고 C형 간염 바이러스(Hepatitis C virus; HCV)는 만성 감염질환을 일으키는 대표적인 바이러스들이다. 인체내 감염시 임상적 진행경과에 따른 바이러스 특이 T림프구의 항바이러스 기능변화 및 바이러스의 체내 지속성과 T림프구에 발현되는 다양한 면역인자(e.g., CD28, CD25, FoxP3, PD-1, CTLA-4)들과의 구체적인 상관관계는 최근 많은 국내외 연구진들을 통해 연구되고 있다. 그 중 FoxP3 (forkhead box P3), PD-1 (programmed death-1) 그리고 CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)는 T림프구에서 발현되는 면역조절인자로 만성 바이러스성 감염시 그 발현이 증가되는 것으로 관찰되었으며, 항바이러스 작용을 가지는 T림프구의 기능결핍과 밀접한 상관관계가 있는 것으로 알려져 있다. 본 총설에서는 만성적인 HIV, HBV, 그리고 HCV 감염에서 바이러스 특이 T림프구에서 발현되는 FoxP3, PD1, 그리고 CTLA-4의 발현변화와 각 질환의 임상적 진행경과와의 상관성, 그리고 이들 발현이 T림프구의 항바이러스 기능에 미치는 영향 등을 중심으로 기술하였다.

• The Plant Pathology Journal
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• 제33권1호
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• pp.53-65
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• 2017

Barley yellow dwarf virus (BYDV) belongs to Luteovirus and is limited only at phloem related tissues. An open reading frame (ORF) 4 of BYDV codes for the movement protein (MP) of BYDV gating plasmodesmata (PD) to facilitate virus movement. Like other Luteoviruses, ORF 4 of BYDV is embedded in the ORF3 but expressed from the different reading frame in leaky scanning manner. Although MP is a very important protein for systemic infection of BYDV, there was a little information. In this study, MP was characterized in terms of subcellular localization and programmed cell death (PCD). Gene of MP or its mutant (ΔMP) was expressed by Agroinfiltration method. MP was clearly localized at the nucleus and the PD, but ΔMP which was deleted distal N-terminus of MP showed no localization to PD exhibited the different target with original MP. In addition to PD localization, MP appeared associated with small granules in cytoplasm whereas ΔMP did not. MP associated with PD and small granules induced PCD, but ΔMP showed no association with PD and small granules did not exhibit PCD. Based on this study, the distal N-terminal region within MP is seemingly responsible for the localization of PD and the induction small granules and PCD induction. These results suggest that subcellular localization of BYDV MP may modulate the PCD in Nicotiana benthamiana.