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The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma.

ABSTRACT: Programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) are target molecules for immunotherapy in non-small cell lung cancer. PD-L1 is expressed not only in cancer cells, but also on macrophages, and has been suggested to contribute to macrophage-mediated immune suppression. We examined the clinical significance of PD-L1 expression on macrophages in human lung adenocarcinoma. The mechanism of PD-L1 overexpression on macrophages was investigated by means of cell culture studies and animal studies. The results showed that high PD-L1 expression on macrophages was correlated with the presence of EGFR mutation, a lower cancer grade, and a shorter cancer-specific overall survival. In an in vitro study using lung cancer cell lines and human monocyte-derived macrophages, the conditioned medium from cancer cells was found to up-regulate PD-L1 expression on macrophages via STAT3 activation, and a cytokine array revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) was a candidate factor that induced PD-L1 expression. Culture studies using recombinant GM-CSF, neutralizing antibody, and inhibitors indicated that PD-L1 overexpression was induced via STAT3 activation by GM-CSF derived from cancer cells. In a murine Lewis lung carcinoma model, anti-GM-CSF therapy inhibited cancer development via the suppression of macrophage infiltration and the promotion of lymphocyte infiltration into cancer tissue; however, the PD-L1 expression on macrophages remained unchanged. PD-L1 overexpression on macrophages via the GM-CSF/STAT3 pathway was suggested to promote cancer progression in lung adenocarcinoma. Cancer cell-derived GM-CSF might be a promising target for anti-lung cancer therapy.

SUBMITTER: Shinchi Y

PROVIDER: S-EPMC8963674 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma.

Shinchi Yusuke Y Ishizuka Shiho S Komohara Yoshihiro Y Matsubara Eri E Mito Remi R Pan Cheng C Yoshii Daiki D Yonemitsu Kimihiro K Fujiwara Yukio Y Ikeda Koei K Tamada Koji K Sakagami Takuro T Suzuki Makoto M

Cancer immunology, immunotherapy : CII 20220329 11

Programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) are target molecules for immunotherapy in non-small cell lung cancer. PD-L1 is expressed not only in cancer cells, but also on macrophages, and has been suggested to contribute to macrophage-mediated immune suppression. We examined the clinical significance of PD-L1 expression on macrophages in human lung adenocarcinoma. The mechanism of PD-L1 overexpression on macrophages was investigated by means of cell culture studies and animal studie ...[more]

PMID: 35352168

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Project description:ObjectivesThis study aimed to assess the intrinsic impacts of the expression of PD-L1 on postoperative recurrence and the prognosis in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas.Patients and methodsData from 221 surgically resected pathological stage IA-IIIA lung adenocarcinomas, collected between 2017 and 2019, were analyzed. This included measurements of EGFR mutations and the PD-L1 expression. Recurrence-free survival (RFS) and overall survival (OS) were estimated using a Kaplan-Meier analysis and log-rank test. The independent risk factors for RFS were assessed using univariate and multivariate analyses.ResultsAmong the patients, 140 were PD-L1-negative (<1%), while 81 were PD-L1-positive (≥1%). PD-L1 positivity was significantly associated with male sex (p=0.038), smoking habit (p=0.005), ND2 lymph node dissection (p=0.013), higher malignant subtype (p=0.003), higher histological grade (p=0.001), and advanced pathological stage (p=0.004). Conversely, EGFR mutations were more common in the PD-L1-negative group than in the PD-L1-positive group (p=0.006). Patients were categorized into four groups based on their EGFR mutation status and PD-L1 expression status: PD-L1-positive (≥1%) with or without EGFR mutations (EGFR(+)/PD-L1≥1% or EGFR (-)/PD-L1≥1%), and PD-L1-negative (<1%) with or without EGFR mutations (EGFR(+)/PD-L1<1% or EGFR (-)/PD-L1<1%). Among these groups, EGFR(+)/PD-L1≥1% cases exhibited the worst 5-year RFS (log-rank, p=0.010), while there was no significant difference in 5-year OS (log-rank, p=0.122). Furthermore, a multivariate analysis revealed that PD-L1 positivity was an independent significant factor for RFS in EGFR-mutated lung adenocarcinoma (p=0.013).ConclusionPD-L1 positivity emerged as an independent risk factor for RFS in patients with EGFR-mutant resected lung adenocarcinoma. These findings may provide valuable insights into the prognostic impact of PD-L1 expression and guide the implementation of postoperative adjuvant therapy in this patient population.

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Dataset Information

The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma.

Publications

The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma.

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