The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy

Yuan, Wei; Zhao, Qiyi; Gao, Zhiliang; Lao, Xiang-Ming; Lin, Wei-Ming; Chen, Dongping; Mu, Ming; Huang, Chun-Xiang; Liu, Zhengyu; Li, Bo; Zheng, Limin; Kuang, Dong-Ming

doi:10.1172/jci127726

Cited by 91 publications

(72 citation statements)

References 62 publications

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“…This may be due to different mechanisms of PD‐L1 induction by macrophages in cancer cells. It has also been reported that tumor PD‐L1 expression is enhanced by TNF‐α from TAM in pancreatic cancer and NF‐κB signal elicited by macrophage inflammatory responses, including production of TNF‐α and IL‐1β, can trigger PD‐L1 expression in hepatocellular carcinoma cells . In this study, we identified TGF‐β as an additional key inducer of PD‐L1 in both A549 and H1975 cells.…”

Section: Discussionsupporting

confidence: 85%

Infiltration of tumor‐associated macrophages is involved in tumor programmed death‐ligand 1 expression in early lung adenocarcinoma

et al. 2020

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Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8 + cytotoxic T cells and FoxP3 + regulatory T cells. Among these immune cells, TAM and CD8 + T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8 + T cells are known to induce tumor PD-L1 expression via interferon-ɣ production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8 + T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-β inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer. K E Y W O R D SB7-H1 antigen, macrophages, non-small-cell lung carcinoma, transforming growth factor beta, tumor microenvironment

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Section: Discussionsupporting

confidence: 85%

Infiltration of tumor‐associated macrophages is involved in tumor programmed death‐ligand 1 expression in early lung adenocarcinoma

et al. 2020

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“…In fact, a previous study has suggested that there may be an immune interaction between pleural effusion tumor cells and macrophages [22]. Moreover, studies have confirmed that both macrophages and T cells in the tumor immune microenvironment can induce tumor cells to express PD-L1 through their distinct patterns [33,34]. Therefore, it is reasonable to believe that PD-L1 expression in tumor cells in pleural effusion may be enhanced by an activated immune response.…”

Section: Discussionmentioning

confidence: 96%

Cytology cell blocks from malignant pleural effusion are good candidates for PD-L1 detection in advanced NSCLC compared with matched histology samples

Zou

Tang

et al. 2020

BMC Cancer

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Background: Detection of programmed cell death ligand-1 (PD-L1) by immunohistochemistry (IHC) has been commonly used to predict the efficacy of treatment with PD-1/PD-L1 inhibitors. However, there is limited literature regarding the reliability of PD-L1 testing using malignant pleural effusion (MPE) cell blocks. Here, we assess PD-L1 expression in sections from MPE cell blocks and evaluate the value of IHC double staining in the interpretation of PD-L1 expression. Methods: In all, 124 paired formalin-fixed tissues from advanced NSCLC patients, including MPE cell blocks and matched histology samples, were included. PD-L1 expression was assessed using the SP263 assay, and the tumor proportion score (TPS) and the staining intensity were evaluated. PD-L1 staining results were also compared between IHC double and single staining techniques. Results: PD-L1 expression was concordant in most paired cases (86/101, 85.1%) among three TPS cutoffs (<1%, 1-49% and ≥ 50%), with a kappa value of 0.774. Moreover, a significant difference in PD-L1 expression between MPE cell blocks and biopsy samples was observed (p = 0.005). For the 15 discordant pairs, 13 MPE cell block samples showed increased expression of PD-L1. Compared with the standard IHC single PD-L1 assay, double staining with anti-TTF-1 and anti-PD-L1 revealed a negative effect on PD-L1 expression testing and resulted in weaker staining intensity and a lower TPS (p = 0.000). Conclusions: MPE cell block samples are good candidates for PD-L1 expression detection in advanced NSCLC patients. The mechanism and clinical significance of the higher PD-L1 expression rate in MPE cell blocks compared with small biopsy samples remain to be evaluated prospectively.

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“…PD-L1 can be expressed in tumor microenvironment cells and can inhibit the activation of T cells through binding to PD-1, which also weakens the entire immune system of patients [33][34][35]. Immune checkpoint therapy prevents PD-1/PD-L1 binding in tumors and restores the cytotoxicity of T cells [36].…”

Section: Discussionmentioning

confidence: 99%

Second-line treatment strategy for urothelial cancer patients who progress or are unfit for cisplatin therapy: a network meta-analysis

Wang

Liu

Fang

et al. 2019

Preprint

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Background Second-line treatment for urothelial carcinoma (UC) patients is used if progression or failure after platinum-based chemotherapy occurs or if patients are cisplatin-unfit. However, there is still no widely accepted treatment strategy. We aimed to analyze the effectiveness and safety of second-line treatment strategies for UC patients. Methods The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) that included UC patients who were cisplatin-ineligible or unfit up to April 19, 2019. The primary outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results Thirteen trials that assessed 3502 UC patients were included. This study divided the network comparisons into three parts. The first part contained studies comparing taxanes and other interventions; the second part assessed investigator’s choice chemotherapy (ICC)-related comparisons; and the third part assessed best support care (BSC). In the OS results of the first part, pembrolizumab (87.5%), ramucirumab plus docetaxel (74.6%), and atezolizumab (71.1%) had a relative advantage. Pembrolizumab also had advantages in ORR and severe adverse effect (SAE) results. Vinflunine and ramucirumab plus docetaxel had a relatively high surface under the cumulative ranking (SUCRA) rank by exploratory cluster analysis. Conclusions This study concluded that atezolizumab and pembrolizumab are superior to other treatments, mainly in OS results, but no treatment confers a significant advantage in PFS. Pembrolizumab still has relative advantages in ORR and SAE results compared to ICC.

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The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy

Cited by 91 publications

References 62 publications

Infiltration of tumor‐associated macrophages is involved in tumor programmed death‐ligand 1 expression in early lung adenocarcinoma

Infiltration of tumor‐associated macrophages is involved in tumor programmed death‐ligand 1 expression in early lung adenocarcinoma

Cytology cell blocks from malignant pleural effusion are good candidates for PD-L1 detection in advanced NSCLC compared with matched histology samples

Second-line treatment strategy for urothelial cancer patients who progress or are unfit for cisplatin therapy: a network meta-analysis

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