Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

François Xavier Danlos; Matthieu Texier; Bastien Job; Severine Mouraud; Lydie Cassard; Capucine Baldini; Andrea Varga; Andrey A. Yurchenko; Audrey Rabeau; Stéphane Champiat; Diane Letourneur; Delphine Bredel; Sandrine Susini; Yuna Blum; Aurelien Parpaleix; Cedric Parlavecchio; Lambros Tselikas; Jean Eudes Fahrner; Anne Gaelle Goubet; Mathieu Rouanne; Saloomeh Rafie; Alae Abbassi; Ines Kasraoui; Marie Breckler; Siham Farhane; Samy Ammari; Salim Laghouati; Anas Gazzah; Ludovic Lacroix; Benjamin Besse; Nathalie Droin; Marc Deloger; Sophie Cotteret; Julien Adam; Laurence Zitvoge; Sergey I. Nikolaev; Nathalie Chaput; Christophe Massard; Jean Charles Soria; Carlos Gomez-Roca; Gerard Zalcman; David Planchard; Aurelien Marabelle

doi:10.1158/2159-8290.CD-22-0886

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

François Xavier Danlos, Matthieu Texier, Bastien Job, Severine Mouraud, Lydie Cassard, Capucine Baldini, Andrea Varga, Andrey A. Yurchenko, Audrey Rabeau, Stéphane Champiat, Diane Letourneur, Delphine Bredel, Sandrine Susini, Yuna Blum, Aurelien Parpaleix, Cedric Parlavecchio, Lambros Tselikas, Jean Eudes Fahrner, Anne Gaelle Goubet, Mathieu RouanneSaloomeh Rafie, Alae Abbassi, Ines Kasraoui, Marie Breckler, Siham Farhane, Samy Ammari, Salim Laghouati, Anas Gazzah, Ludovic Lacroix, Benjamin Besse, Nathalie Droin, Marc Deloger, Sophie Cotteret, Julien Adam, Laurence Zitvoge, Sergey I. Nikolaev, Nathalie Chaput, Christophe Massard, Jean Charles Soria, Carlos Gomez-Roca, Gerard Zalcman, David Planchard, Aurelien Marabelle

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

9 Citations (Scopus)

Résumé

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

langue originale	Anglais
Pages (de - à)	858-879
Nombre de pages	22
journal	Cancer Discovery
Volume	13
Numéro de publication	4
Les DOIs	https://doi.org/10.1158/2159-8290.CD-22-0886
état	Publié - 1 avr. 2023

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10.1158/2159-8290.CD-22-0886

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Danlos, F. X., Texier, M., Job, B., Mouraud, S., Cassard, L., Baldini, C., Varga, A., Yurchenko, A. A., Rabeau, A., Champiat, S., Letourneur, D., Bredel, D., Susini, S., Blum, Y., Parpaleix, A., Parlavecchio, C., Tselikas, L., Fahrner, J. E., Goubet, A. G., ... Marabelle, A. (2023). Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma. Cancer Discovery, 13(4), 858-879. https://doi.org/10.1158/2159-8290.CD-22-0886

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title = "Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma",

abstract = "Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas{\textquoteright} primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.",

author = "Danlos, {Fran{\c c}ois Xavier} and Matthieu Texier and Bastien Job and Severine Mouraud and Lydie Cassard and Capucine Baldini and Andrea Varga and Yurchenko, {Andrey A.} and Audrey Rabeau and St{\'e}phane Champiat and Diane Letourneur and Delphine Bredel and Sandrine Susini and Yuna Blum and Aurelien Parpaleix and Cedric Parlavecchio and Lambros Tselikas and Fahrner, {Jean Eudes} and Goubet, {Anne Gaelle} and Mathieu Rouanne and Saloomeh Rafie and Alae Abbassi and Ines Kasraoui and Marie Breckler and Siham Farhane and Samy Ammari and Salim Laghouati and Anas Gazzah and Ludovic Lacroix and Benjamin Besse and Nathalie Droin and Marc Deloger and Sophie Cotteret and Julien Adam and Laurence Zitvoge and Nikolaev, {Sergey I.} and Nathalie Chaput and Christophe Massard and Soria, {Jean Charles} and Carlos Gomez-Roca and Gerard Zalcman and David Planchard and Aurelien Marabelle",

year = "2023",

month = apr,

day = "1",

doi = "10.1158/2159-8290.CD-22-0886",

language = "English",

volume = "13",

pages = "858--879",

journal = "Cancer Discovery",

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Danlos, FX, Texier, M, Job, B, Mouraud, S, Cassard, L, Baldini, C, Varga, A, Yurchenko, AA, Rabeau, A, Champiat, S, Letourneur, D, Bredel, D, Susini, S, Blum, Y, Parpaleix, A, Parlavecchio, C, Tselikas, L, Fahrner, JE, Goubet, AG, Rouanne, M, Rafie, S, Abbassi, A, Kasraoui, I, Breckler, M, Farhane, S, Ammari, S, Laghouati, S, Gazzah, A, Lacroix, L, Besse, B, Droin, N, Deloger, M, Cotteret, S, Adam, J, Zitvoge, L, Nikolaev, SI, Chaput, N, Massard, C, Soria, JC, Gomez-Roca, C, Zalcman, G, Planchard, D & Marabelle, A 2023, 'Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma', Cancer Discovery, VOL. 13, Numéro 4, p. 858-879. https://doi.org/10.1158/2159-8290.CD-22-0886

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma. / Danlos, François Xavier; Texier, Matthieu; Job, Bastien et al.
Dans: Cancer Discovery, Vol 13, Numéro 4, 01.04.2023, p. 858-879.

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

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T1 - Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

AU - Danlos, François Xavier

AU - Texier, Matthieu

AU - Job, Bastien

AU - Mouraud, Severine

AU - Cassard, Lydie

AU - Baldini, Capucine

AU - Varga, Andrea

AU - Yurchenko, Andrey A.

AU - Rabeau, Audrey

AU - Champiat, Stéphane

AU - Letourneur, Diane

AU - Bredel, Delphine

AU - Susini, Sandrine

AU - Blum, Yuna

AU - Parpaleix, Aurelien

AU - Parlavecchio, Cedric

AU - Tselikas, Lambros

AU - Fahrner, Jean Eudes

AU - Goubet, Anne Gaelle

AU - Rouanne, Mathieu

AU - Rafie, Saloomeh

AU - Abbassi, Alae

AU - Kasraoui, Ines

AU - Breckler, Marie

AU - Farhane, Siham

AU - Ammari, Samy

AU - Laghouati, Salim

AU - Gazzah, Anas

AU - Lacroix, Ludovic

AU - Besse, Benjamin

AU - Droin, Nathalie

AU - Deloger, Marc

AU - Cotteret, Sophie

AU - Adam, Julien

AU - Zitvoge, Laurence

AU - Nikolaev, Sergey I.

AU - Chaput, Nathalie

AU - Massard, Christophe

AU - Soria, Jean Charles

AU - Gomez-Roca, Carlos

AU - Zalcman, Gerard

AU - Planchard, David

AU - Marabelle, Aurelien

PY - 2023/4/1

Y1 - 2023/4/1

N2 - Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

AB - Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

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DO - 10.1158/2159-8290.CD-22-0886

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