IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade

Our plain-English summary of IFN-γ upregulates membranous and soluble PD-L1 in mesothelioma cells: potential implications for the clinical response to PD-1/PD-L1 blockade, by M.P. Pistillo, R. Carosio, B. Banelli, et al (Cellular & Molecular Immunology, 2020).

The study

• Authors: M.P. Pistillo, R. Carosio, B. Banelli, A. Morabito, L. Mastracci, P. Ferro, S. Varesano, R. Venè, A. Poggi, S. Roncella
• Journal: Cellular & Molecular Immunology
• Published: 2020;17(4):410-411
• Type of article: Letter
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Summary of the article

In this correspondence, the authors examined whether interferon gamma (IFN-γ) increases the cell surface expression and release of programmed death-ligand-1 (PD-L1) in malignant pleural mesothelioma (MPM) cells. PD-L1 suppresses the antitumor immune response by binding PD-1 on cytotoxic T cells, and it has emerged as a predictive biomarker for PD-1/PD-L1 immune checkpoint blockers (ICBs) in MPM. Three MPM cell lines (MPP89, IST-MES1 and IST-MES2) were obtained from the Interlab Cell Line Collection in Genoa, Italy. They were left untreated or treated with 10 ng/ml IFN-γ for 48 hours. PD-L1 was assessed by flow cytometry, Western blot, mRNA levels of the full-length transcript, and ELISA of culture supernatants. IFN-γ increased membrane PD-L1 by 4.02-, 7.76- and 11.40-fold in MPP89, IST-MES1 and IST-MES2, respectively. This was accompanied by increased PD-L1 protein in cell lysates and higher full-length transcript levels (mean fold change 7.41, 21.61 and 15.84). All three cell lines spontaneously secreted low amounts of soluble PD-L1 (sPD-L1), and IFN-γ increased sPD-L1 in supernatants by 9.29-, 4.87- and 10.53-fold. The authors hypothesized that the high levels of IFN-γ released by tumor-infiltrating lymphocytes in MPM might contribute to resistance to ICBs by increasing surface and soluble PD-L1. For example, sPD-L1 might trap anti-PD-L1 antibodies. They stated that future investigations are needed to determine whether blocking IFN-γ signaling could increase the efficacy of immunotherapy in MPM patients.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This short research letter reported a laboratory experiment on three cell lines grown from malignant pleural mesothelioma (MPM), named MPP89, IST-MES1 and IST-MES2. It did not study patients or asbestos exposure. The authors treated the cells with interferon gamma (IFN-γ), an immune signaling substance, at 10 ng/ml for 48 hours. They then measured PD-L1, a tumor-cell protein that can switch off attacking immune cells and that some immunotherapy drugs target. After treatment, PD-L1 on the cell surface rose 4.02-, 7.76- and 11.40-fold in the three lines. The authors said this rise appeared to depend on the cells making more PD-L1 protein. The genetic message (mRNA) for full-length PD-L1 rose on average 7.41-, 21.61- and 15.84-fold. Even untreated, all three lines released small amounts of a soluble form of PD-L1 into the culture fluid, and IFN-γ raised this 9.29-, 4.87- and 10.53-fold. The authors hypothesized that high IFN-γ levels released by immune cells within mesothelioma tumors might contribute to resistance to drugs that block PD-1 or PD-L1. They said future studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cancer cell lines, published as a correspondence letter
• Who was studied: Three malignant pleural mesothelioma cell lines (MPP89, IST-MES1, IST-MES2) obtained from the Interlab Cell Line Collection, Genoa, Italy; no human participants
• Exposure: Interferon gamma (IFN-γ) at 10 ng/ml for 48 hours, compared with untreated cells; no asbestos or fiber exposure was studied
• Main results:
  • IFN-γ increased cell-surface (membrane) PD-L1 by 4.02-fold in MPP89, 7.76-fold in IST-MES1 and 11.40-fold in IST-MES2 cells (flow cytometry)
  • The surface increase appeared to depend on increased synthesis of PD-L1 protein (Western blot of cell lysates)
  • mRNA for full-length membranous PD-L1 rose with IFN-γ, mean fold change 7.41 in MPP89, 21.61 in IST-MES1 and 15.84 in IST-MES2 cells
  • All three cell lines spontaneously secreted low amounts of soluble PD-L1 (sPD-L1) without treatment
  • IFN-γ increased sPD-L1 in culture supernatants by 9.29-fold in MPP89, 4.87-fold in IST-MES1 and 10.53-fold in IST-MES2 cells (ELISA)
• The authors' conclusion: The authors hypothesized that high IFN-γ levels released by tumor-infiltrating lymphocytes in MPM might, by increasing surface and released PD-L1, contribute to resistance to PD-1/PD-L1 blocking drugs. They said future work is needed on whether blocking IFN-γ signaling could improve immunotherapy.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, PD-1/PD-L1, Pleural Mesothelioma, Biomarker, Tumor-Infiltrating Lymphocytes, Immunotherapy.

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