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Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer
Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizu...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139811/ https://www.ncbi.nlm.nih.gov/pubmed/32178474 http://dx.doi.org/10.3390/cancers12030666 |
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author | Cavazzoni, Andrea Digiacomo, Graziana Alfieri, Roberta La Monica, Silvia Fumarola, Claudia Galetti, Maricla Bonelli, Mara Cretella, Daniele Barili, Valeria Zecca, Alessandra Giovannetti, Elisa Fiorentino, Michelangelo Tiseo, Marcello Petronini, Pier Giorgio Ardizzoni, Andrea |
author_facet | Cavazzoni, Andrea Digiacomo, Graziana Alfieri, Roberta La Monica, Silvia Fumarola, Claudia Galetti, Maricla Bonelli, Mara Cretella, Daniele Barili, Valeria Zecca, Alessandra Giovannetti, Elisa Fiorentino, Michelangelo Tiseo, Marcello Petronini, Pier Giorgio Ardizzoni, Andrea |
author_sort | Cavazzoni, Andrea |
collection | PubMed |
description | Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens. |
format | Online Article Text |
id | pubmed-7139811 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71398112020-04-10 Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer Cavazzoni, Andrea Digiacomo, Graziana Alfieri, Roberta La Monica, Silvia Fumarola, Claudia Galetti, Maricla Bonelli, Mara Cretella, Daniele Barili, Valeria Zecca, Alessandra Giovannetti, Elisa Fiorentino, Michelangelo Tiseo, Marcello Petronini, Pier Giorgio Ardizzoni, Andrea Cancers (Basel) Article Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens. MDPI 2020-03-12 /pmc/articles/PMC7139811/ /pubmed/32178474 http://dx.doi.org/10.3390/cancers12030666 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cavazzoni, Andrea Digiacomo, Graziana Alfieri, Roberta La Monica, Silvia Fumarola, Claudia Galetti, Maricla Bonelli, Mara Cretella, Daniele Barili, Valeria Zecca, Alessandra Giovannetti, Elisa Fiorentino, Michelangelo Tiseo, Marcello Petronini, Pier Giorgio Ardizzoni, Andrea Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title | Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title_full | Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title_fullStr | Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title_full_unstemmed | Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title_short | Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer |
title_sort | pemetrexed enhances membrane pd-l1 expression and potentiates t cell-mediated cytotoxicity by anti-pd-l1 antibody therapy in non-small-cell lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139811/ https://www.ncbi.nlm.nih.gov/pubmed/32178474 http://dx.doi.org/10.3390/cancers12030666 |
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