<scp>PD</scp>‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis

Tsukamoto, M; Imai, Katsunori; Ishimoto, Takatsugu; Komohara, Yoshihiro; Yamashita, Yo‐ichi; Nakagawa, Shigeki; Umezaki, Naoki; Yamao, Takanobu; Miyata, Tatsunori; Arima, Kei; Okabe, Hidetoshi; Baba, Yoshifumi; Chikamoto, Akira; Ishiko, Takatoshi; Hirota, Masahiko

doi:10.1111/cas.13874

Cited by 54 publications

(48 citation statements)

References 39 publications

(77 reference statements)

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“…In addition to these extrinsic stimuli, intrinsic genetic alteration such as PD‐L1 gene amplification and deletion of the 3′‐UTR may influence PD‐L1 expression . We previously found that there was a significant correlation between PD‐L1 expression in cancer cells and macrophage infiltration in the tumor microenvironment, and macrophage‐derived tumor necrosis factor‐α was revealed to induce PD‐L1 overexpression via NF‐κB signal activation in pancreatic cancer . In the present study, macrophage infiltration was also detected by Iba‐1 IHC as described previously .…”

Section: Discussionmentioning

confidence: 56%

Accurate expression of PD‐L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry

et al. 2019

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The percentage of programmed death ligand 1 (PD‐L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti‐PD‐1/PD‐L1 therapy in lung cancer. PD‐L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD‐L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD‐L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD‐L1 expression was negative in 169 patients (73.2%), 1%‐49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD‐L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD‐L1 expression was associated with high‐grade cancer cells and in higher stage cancer. PD‐L2 was negative in 109 patients (47.2%), 1%‐49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD‐L2‐positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty‐five patients (15.2%) were positive for both PD‐L1 and PD‐L2, whereas 81 patients (35.1%) were negative for both PD‐L1 and PD‐L2. Log‐rank analysis showed that progression‐free survival and overall survival were significantly the longest in the PD‐L1‐negative and PD‐L2‐positive groups (P < .0001 and P = .0120). We observed lower PD‐L1 or PD‐L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD‐L1 or PD‐L2 expression specifically in cancer cells.

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Section: Discussionmentioning

confidence: 56%

Accurate expression of PD‐L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry

et al. 2019

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“…TAM are known to show an immunosuppressive phenotype by attracting other immunosuppressive cells such as regulatory T cells, myeloid‐derived suppressor cells and type 2 helper T cells . Recently, TAM infiltration has been reported to be associated with the upregulation of PD‐L1 expression in gastric and pancreatic cancer, but its molecular mechanism is limited. The present study is the first report describing the association between TAM infiltration and tumor PD‐L1 expression in early lung AC, and to further show that TAM induced PD‐L1 expression on tumor cells via TGF‐β using an in vitro co–culture system.…”

Section: Discussionmentioning

confidence: 99%

“…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: Discussionmentioning

confidence: 99%

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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“…The specific mechanism of PD‐L1 regulation in pancreatic cancer has not been elucidated fully. Existing reports show that tumor necrosis factor‐α, secreted by macrophages, increases PD‐L1 expression in pancreatic cancer . Previously, we found that the RB–p65 axis , FUBP1–Myc axis , HAT1–BRD4 axis or HDAC3 regulated PD‐L1 expression in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 68%

GNG12 regulates PD‐L1 expression by activating NF‐κB signaling in pancreatic ductal adenocarcinoma

Jin

Zou

et al. 2020

FEBS Open Bio

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors in the digestive system. A greater understanding of the pathogenesis of PDAC may facilitate the search for new therapeutic targets. Guanine nucleotide‐binding protein subunit gamma‐12 (GNG12) belongs to the G protein family and participates in the modulation of the inflammatory signaling cascade. However, the cancer‐related function and clinical relevance of GNG12 in PDAC have not previously been reported. Here, we investigated the clinical significance of GNG12 in PDAC using the Oncomine web tool, the gene expression profiling interactive analysis tool and tissue microarray (TMA). GNG12 expression was observed to be higher in PDAC patient specimens than in nontumor pancreatic tissues, and high expression of GNG12 was associated with poor prognosis. We subsequently show that GNG12 promotes pancreatic cancer cell growth in vivo and in vitro, as evaluated using 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium, inner salt assays, colony formation assays and a xenograft mouse model. Furthermore, our results suggest that GNG12 activates nuclear factor‐κB signaling and modulates the immune response. Collectively, our findings suggest that GNG12 may be suitable as a new prognosis‐related biomarker and a promising target for treatment of pancreatic cancer.

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PD‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis

Cited by 54 publications

References 39 publications

Accurate expression of PD‐L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry

Accurate expression of PD‐L1/L2 in lung adenocarcinoma cells: A retrospective study by double immunohistochemistry

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

GNG12 regulates PD‐L1 expression by activating NF‐κB signaling in pancreatic ductal adenocarcinoma

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