PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis

Que, Yi; Xiao, Wei; Guan, Yuan; Liang, Yao; Shu, Yan; Chen, Huo Ying; Li, Qiao Qiao; Xu, Bu Shu; Zhang, Xing

doi:10.7150/jca.18683

Cited by 87 publications

(73 citation statements)

References 39 publications

(34 reference statements)

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“…A previous report has shown that PD-L1 expression in SM (22,23), and all types of melanoma (24) is associated with CD8 + lymphocytes, consistent with our findings. Furthermore, PD-L1 expression is associated with FOXp3 + lymphocytes in sarcoma (17) and breast cancer (25), consistent with our results. CD8 + lymphocytes as well as PD-L1 expression in tumor cells might be candidate predictive biomarkers for the CIC response.…”

Section: Discussionsupporting

confidence: 92%

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PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

et al. 2020

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Gastrointestinal melanoma (GM) is a rare but aggressive type of malignant melanoma arising in the gastrointestinal tract. An anti-programmed cell death protein 1 (PD-1) antibody markedly improves prognosis in patients with melanoma. However, little is known regarding the expression of immune-oncology biomarkers in GM compared with skin melanoma (SM), especially in the Asian population. the present study examined clinicopathological characteristics, PD-L1 and HLA expression, and immune-oncology marker expression in 10 cases of GM and 31 cases of SM. Patients with GM exhibited significantly higher incidences of lymph node and distant metastases than patients with SM (P=0.0448 and P=0.0247, respectively). The infiltration of CD8 + lymphocytes was significantly higher in GM than in SM (P=0.0231). The infiltration of PD-1 + lymphocytes was higher in GM than in SM, but the difference was not significant (P=0.0975). PD-L1-positive melanoma exhibited a higher proportion of BRAF V600E-positive melanoma than PD-L1-negative melanoma (P=0.0317; 39.4 and 0%, respectively). PD-L1-positive melanoma exhibited significantly higher rates of CD8 + and FOXp3 + lymphocyte infiltration than PD-L1-negative melanoma (P=0.0221 and P=0.0463, respectively). By contrast, PD-1 + lymphocytes did not differ between PD-L1-positive and-negative cases. Furthermore, HLA-positive melanoma exhibited higher proportions of PD-1 (P=0.0101; 53.7 and 15.4%) and CD8 than HLA-negative melanoma (P= 0.0818; 66.7 and 38.2%). These results provided useful information regarding tumor immunity in GM and SM and may contribute to the development of treatment strategies for GM.

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Section: Discussionsupporting

confidence: 92%

“…Patients with PD-L1-positive sarcoma are younger than those with PD-L1-negative sarcoma (17), as observed for melanoma in the present study. In contrast, patients with HLA-positive melanomas were older than those with HLA-negative melanomas in the present study.…”

Section: Discussionsupporting

confidence: 79%

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

et al. 2020

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“…Although CD4+ lymphocytes did not show any association with the prognosis of patients with SS, in our study, a higher infiltration of FOXP3+ lymphocytes was significantly associated with a better OS. However, Que et al evaluated the infiltration of FOXP3+ lymphocytes in 163 cases of soft tissue sarcoma, including 21 cases of SS, and showed that a higher infiltration of FOXP3+ lymphocytes was associated with a poor prognosis. This result is markedly different from ours.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of the tumor immune microenvironment in synovial sarcoma

et al. 2018

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The association between the immune status within the tumor microenvironment and prognosis in synovial sarcoma is not well understood. We aimed to investigate the tumor immune microenvironment and analyze its prognostic impact for patients with synovial sarcoma. A total of 36 primary patients who were treated in our institution were retrospectively evaluated. Infiltration of lymphocytes (CD4+, CD8+, and FOXP3+), CD163+ macrophages, and expression of human leukocyte antigen (HLA) class I and programmed death ligand 1 (PD‐L1) were evaluated by immunohistochemistry. Moreover, we investigated PD‐L1 and programmed death ligand 2 (PD‐L2) mRNA expression in 19 of the 36 cases, using real‐time PCR. The Kaplan‐Meier method was used to estimate overall survival and progression‐free survival. Infiltration of lymphocytes and macrophages varied among the patients. Furthermore, the expression of HLA class I was negative or downregulated in 11 specimens. No PD‐L1 expression was observed using immunohistochemistry. Moreover, although PD‐L1 mRNA expression was observed in 18 of 19 specimens, the expression level was low. A higher infiltration of CD8+ or FOXP3+ lymphocytes in patients was associated with a favorable overall survival. In addition, a higher infiltration of CD163+ macrophages indicated a significantly worse overall and progression‐free survival. Infiltration of CD4+ lymphocytes, HLA class I, PD‐L1, and PD‐L2 expression were not associated with patient prognosis. This represents the first report investigating the tumor immune microenvironment as a prognostic factor in synovial sarcoma, indicating that CD163+ macrophages are associated with tumor progression. Our results underscore the clinical significance of the tumor immune microenvironment in synovial sarcoma.

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“…12 In PDAC, it is referred to as cancer-FOXP3 (C-FOXP3), and its function is to mediate immune evasion by recruiting FOXP3+ T cells (Treg cells) via upregulation of CCL5. Interestingly, accumulating evidence has linked the coexistence of tumor-associated PD-L1 and Treg cell infiltration in multiple tumors, including PDAC, [14][15][16] suggesting that C-FOXP3 may be correlated with PD-L1 expression in PDAC. The regulatory mechanism(s) of PD-L1 expression on pancreatic cancer cells remains poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

Wang

Wei

et al. 2020

Sig Transduct Target Ther

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High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8 + T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.

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PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis

Cited by 87 publications

References 39 publications

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

Prognostic impact of the tumor immune microenvironment in synovial sarcoma

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

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