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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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