Immunodynamics of explanted human tumors for immuno‐oncology

Report29 December 2020Open Access Source DataTransparent process Immunodynamics of explanted human tumors for immuno-oncology Agathe Dubuisson Agathe Dubuisson orcid.org/0000-0002-7526-0769 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Jean-Eudes Fahrner Jean-Eudes Fahrner orcid.org/0000-0001-6581-8418 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Transgene S.A, Illkirch-Graffenstaden, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Anne-Gaëlle Goubet Anne-Gaëlle Goubet Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Safae Terrisse Safae Terrisse Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Nicolas Voisin Nicolas Voisin Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Charles Bayard Charles Bayard Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Sebastien Lofek Sebastien Lofek Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Damien Drubay Damien Drubay Institut Gustave Roussy, Villejuif, France Service de Biostatistique et d'epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France Oncostat U1018, Inserm, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France Search for more papers by this author Delphine Bredel Delphine Bredel Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Séverine Mouraud Séverine Mouraud orcid.org/0000-0003-3264-6298 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Sandrine Susini Sandrine Susini Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Alexandria Cogdill Alexandria Cogdill Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France The University of Texas MD Anderson Cancer Center, Houston, TX, USA Search for more papers by this author Lucas Rebuffet Lucas Rebuffet Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Elise Ballot Elise Ballot Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France Centre de Recherche INSERM LNC-UMR1231, Dijon, France Search for more papers by this author Nicolas Jacquelot Nicolas Jacquelot Institut Gustave Roussy, Villejuif, France Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia Search for more papers by this author Vincent Thomas de Montpreville Vincent Thomas de Montpreville orcid.org/0000-0001-7490-4000 Service d'Anatomie et cytologie pathologiques, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Search for more papers by this author Odile Casiraghi Odile Casiraghi Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Camélia Radulescu Camélia Radulescu Service d'Anatomie et cytologie pathologiques, Hôpital Foch, Suresnes, France Search for more papers by this author Sophie Ferlicot Sophie Ferlicot Service d'Anatomie et cytologie pathologiques, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author David J Figueroa David J Figueroa Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Sapna Yadavilli Sapna Yadavilli Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Jeremy D Waight Jeremy D Waight Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Marc Ballas Marc Ballas Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Axel Hoos Axel Hoos Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Thomas Condamine Thomas Condamine Incyte Research Institute, Wilmington, DE, USA Search for more papers by this author Bastien Parier Bastien Parier Service de Chirurgie urologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author Christophe Gaudillat Christophe Gaudillat Service d'Urologie, Hôpital Saint Joseph, Paris, France Search for more papers by this author Bertrand Routy Bertrand Routy Division of Oncology, Department of Medicine, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada Search for more papers by this author François Ghiringhelli François Ghiringhelli Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France Centre de Recherche INSERM LNC-UMR1231, Dijon, France Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France Search for more papers by this author Lisa Derosa Lisa Derosa Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Ingrid Breuskin Ingrid Breuskin Département de Chirurgie, Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Mathieu Rouanne Mathieu Rouanne Institut Gustave Roussy, Villejuif, France Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Service d'Urologie, Hôpital Foch, Suresnes, France UVSQ – Université Paris Saclay, Versailles, France Search for more papers by this author Fabrice André Fabrice André Institut Gustave Roussy, Villejuif, France Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Cédric Lebacle Cédric Lebacle Service de Chirurgie urologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author Hervé Baumert Hervé Baumert Institut Gustave Roussy, Villejuif, France Search for more papers by this author Marie Wislez Marie Wislez AP-HP, Centre – Université de Paris, Hôpital Cochin, Unité d'Oncologie Thoracique, Service de Pneumologie, Paris, France AP-HP, Hôpitaux Universitaires de l'Est Parisien, Hôpital Tenon, Service de Pneumologie, Paris, France Search for more papers by this author Elie Fadel Elie Fadel Service de Chirurgie Thoracique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Search for more papers by this author Isabelle Cremer Isabelle Cremer Team Inflammation, Complement and Cancer, INSERM, Centre de Recherche des Cordeliers, Paris, France Sorbonne Université, Paris, France Search for more papers by this author Laurence Albiges Laurence Albiges Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Birgit Geoerger Birgit Geoerger orcid.org/0000-0003-4361-3643 Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France Search for more papers by this author Jean-Yves Scoazec Jean-Yves Scoazec Institut Gustave Roussy, Villejuif, France Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Yohann Loriot Yohann Loriot Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Guido Kroemer Guido Kroemer orcid.org/0000-0002-9334-4405 Institut Gustave Roussy, Villejuif, France Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden Search for more papers by this author Aurélien Marabelle Aurélien Marabelle Institut Gustave Roussy, Villejuif, France Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Mélodie Bonvalet Mélodie Bonvalet Institut Gustave Roussy, Villejuif, France Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France Search for more papers by this author Laurence Zitvogel Corresponding Author Laurence Zitvogel [email protected] orcid.org/0000-0003-1596-0998 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Gustave Roussy, Université Paris-Saclay, Villejuif, France Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France Search for more papers by this author Agathe Dubuisson Agathe Dubuisson orcid.org/0000-0002-7526-0769 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Jean-Eudes Fahrner Jean-Eudes Fahrner orcid.org/0000-0001-6581-8418 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Transgene S.A, Illkirch-Graffenstaden, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Anne-Gaëlle Goubet Anne-Gaëlle Goubet Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, FranceThese authors contributed equally to this work as first authors Search for more papers by this author Safae Terrisse Safae Terrisse Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Nicolas Voisin Nicolas Voisin Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Charles Bayard Charles Bayard Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Sebastien Lofek Sebastien Lofek Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Damien Drubay Damien Drubay Institut Gustave Roussy, Villejuif, France Service de Biostatistique et d'epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France Oncostat U1018, Inserm, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France Search for more papers by this author Delphine Bredel Delphine Bredel Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Séverine Mouraud Séverine Mouraud orcid.org/0000-0003-3264-6298 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Sandrine Susini Sandrine Susini Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Alexandria Cogdill Alexandria Cogdill Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France The University of Texas MD Anderson Cancer Center, Houston, TX, USA Search for more papers by this author Lucas Rebuffet Lucas Rebuffet Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Search for more papers by this author Elise Ballot Elise Ballot Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France Centre de Recherche INSERM LNC-UMR1231, Dijon, France Search for more papers by this author Nicolas Jacquelot Nicolas Jacquelot Institut Gustave Roussy, Villejuif, France Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia Search for more papers by this author Vincent Thomas de Montpreville Vincent Thomas de Montpreville orcid.org/0000-0001-7490-4000 Service d'Anatomie et cytologie pathologiques, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Search for more papers by this author Odile Casiraghi Odile Casiraghi Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Camélia Radulescu Camélia Radulescu Service d'Anatomie et cytologie pathologiques, Hôpital Foch, Suresnes, France Search for more papers by this author Sophie Ferlicot Sophie Ferlicot Service d'Anatomie et cytologie pathologiques, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author David J Figueroa David J Figueroa Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Sapna Yadavilli Sapna Yadavilli Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Jeremy D Waight Jeremy D Waight Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Marc Ballas Marc Ballas Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Axel Hoos Axel Hoos Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Search for more papers by this author Thomas Condamine Thomas Condamine Incyte Research Institute, Wilmington, DE, USA Search for more papers by this author Bastien Parier Bastien Parier Service de Chirurgie urologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author Christophe Gaudillat Christophe Gaudillat Service d'Urologie, Hôpital Saint Joseph, Paris, France Search for more papers by this author Bertrand Routy Bertrand Routy Division of Oncology, Department of Medicine, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada Search for more papers by this author François Ghiringhelli François Ghiringhelli Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France Centre de Recherche INSERM LNC-UMR1231, Dijon, France Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France Search for more papers by this author Lisa Derosa Lisa Derosa Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Ingrid Breuskin Ingrid Breuskin Département de Chirurgie, Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Mathieu Rouanne Mathieu Rouanne Institut Gustave Roussy, Villejuif, France Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Service d'Urologie, Hôpital Foch, Suresnes, France UVSQ – Université Paris Saclay, Versailles, France Search for more papers by this author Fabrice André Fabrice André Institut Gustave Roussy, Villejuif, France Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Cédric Lebacle Cédric Lebacle Service de Chirurgie urologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France Search for more papers by this author Hervé Baumert Hervé Baumert Institut Gustave Roussy, Villejuif, France Search for more papers by this author Marie Wislez Marie Wislez AP-HP, Centre – Université de Paris, Hôpital Cochin, Unité d'Oncologie Thoracique, Service de Pneumologie, Paris, France AP-HP, Hôpitaux Universitaires de l'Est Parisien, Hôpital Tenon, Service de Pneumologie, Paris, France Search for more papers by this author Elie Fadel Elie Fadel Service de Chirurgie Thoracique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France Search for more papers by this author Isabelle Cremer Isabelle Cremer Team Inflammation, Complement and Cancer, INSERM, Centre de Recherche des Cordeliers, Paris, France Sorbonne Université, Paris, France Search for more papers by this author Laurence Albiges Laurence Albiges Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Birgit Geoerger Birgit Geoerger orcid.org/0000-0003-4361-3643 Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France Search for more papers by this author Jean-Yves Scoazec Jean-Yves Scoazec Institut Gustave Roussy, Villejuif, France Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Yohann Loriot Yohann Loriot Institut Gustave Roussy, Villejuif, France Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Guido Kroemer Guido Kroemer orcid.org/0000-0002-9334-4405 Institut Gustave Roussy, Villejuif, France Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden Search for more papers by this author Aurélien Marabelle Aurélien Marabelle Institut Gustave Roussy, Villejuif, France Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, France Search for more papers by this author Mélodie Bonvalet Mélodie Bonvalet Institut Gustave Roussy, Villejuif, France Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France Search for more papers by this author Laurence Zitvogel Corresponding Author Laurence Zitvogel [email protected] orcid.org/0000-0003-1596-0998 Institut Gustave Roussy, Villejuif, France Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France Gustave Roussy, Université Paris-Saclay, Villejuif, France Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France Search for more papers by this author Author Information Agathe Dubuisson1,2, Jean-Eudes Fahrner1,2,3, Anne-Gaëlle Goubet1,2, Safae Terrisse1,2, Nicolas Voisin1,2, Charles Bayard1,2, Sebastien Lofek1,2, Damien Drubay1,4,5, Delphine Bredel1,2, Séverine Mouraud1,2, Sandrine Susini1,2, Alexandria Cogdill1,2,6, Lucas Rebuffet1,2, Elise Ballot7,8, Nicolas Jacquelot1,9,10, Vincent Thomas de Montpreville11, Odile Casiraghi12, Camélia Radulescu13, Sophie Ferlicot14, David J Figueroa15, Sapna Yadavilli15, Jeremy D Waight15, Marc Ballas15, Axel Hoos15, Thomas Condamine16, Bastien Parier17, Christophe Gaudillat18, Bertrand Routy19,20, François Ghiringhelli7,8,21, Lisa Derosa1,22, Ingrid Breuskin23, Mathieu Rouanne1,12,24,25, Fabrice André1,26, Cédric Lebacle17, Hervé Baumert1, Marie Wislez27,28, Elie Fadel29, Isabelle Cremer30,31, Laurence Albiges1,22, Birgit Geoerger32, Jean-Yves Scoazec1,12, Yohann Loriot1,22, Guido Kroemer1,33,34,35,36,37, Aurélien Marabelle1,38, Mélodie Bonvalet1,39 and Laurence Zitvogel *,1,2,26,39 1Institut Gustave Roussy, Villejuif, France 2Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France 3Transgene S.A, Illkirch-Graffenstaden, France 4Service de Biostatistique et d'epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France 5Oncostat U1018, Inserm, Université Paris-Saclay, Équipe Labellisée Ligue Contre le Cancer, Villejuif, France 6The University of Texas MD Anderson Cancer Center, Houston, TX, USA 7Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France 8Centre de Recherche INSERM LNC-UMR1231, Dijon, France 9Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia 10Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia 11Service d'Anatomie et cytologie pathologiques, Hôpital Marie Lannelongue, Le Plessis-Robinson, France 12Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France 13Service d'Anatomie et cytologie pathologiques, Hôpital Foch, Suresnes, France 14Service d'Anatomie et cytologie pathologiques, Hôpital Bicêtre, Le Kremlin-Bicêtre, France 15Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA 16Incyte Research Institute, Wilmington, DE, USA 17Service de Chirurgie urologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France 18Service d'Urologie, Hôpital Saint Joseph, Paris, France 19Division of Oncology, Department of Medicine, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada 20Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada 21Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France 22Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France 23Département de Chirurgie, Gustave Roussy, Université Paris-Saclay, Villejuif, France 24Service d'Urologie, Hôpital Foch, Suresnes, France 25UVSQ – Université Paris Saclay, Versailles, France 26Gustave Roussy, Université Paris-Saclay, Villejuif, France 27AP-HP, Centre – Université de Paris, Hôpital Cochin, Unité d'Oncologie Thoracique, Service de Pneumologie, Paris, France 28AP-HP, Hôpitaux Universitaires de l'Est Parisien, Hôpital Tenon, Service de Pneumologie, Paris, France 29Service de Chirurgie Thoracique, Hôpital Marie Lannelongue, Le Plessis-Robinson, France 30Team Inflammation, Complement and Cancer, INSERM, Centre de Recherche des Cordeliers, Paris, France 31Sorbonne Université, Paris, France 32Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France 33Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France 34Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France 35Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France 36Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China 37Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden 38Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, France 39Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France *Corresponding author: Tel: +33 14211655005; E-mail: [email protected] EMBO Mol Med (2021)13:e12850https://doi.org/10.15252/emmm.202012850 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay. Synopsis To predict cancer resistance to PD-1 blockade and design suitable combinations of immunomodulators, a 60-h functional in sitro assay was set up in 43 tumors that allowed calculation of the “Immune Reactivity Score (IRS)” based on 17 TCR-dependent- cytokines/chemokines. Primary resistance to PD-1 blockade could be predicted in vitro and in vivo with ~ 70% accuracy. CXCL10 was the best in situ predictor of IRS score and response to PD-1 blockade in patients. 50% of primary resistance to PD-1 blockade could be overcome by a personalized combinatorial regimen. Hypo-responders to PD-1 blockade could be prevented by combining anti-PD-1 and anti-KIR mAbs. The paper explained Problem Predicting primary resistance to PD-1 blockade and adapting combinatorial regimens in a stratified or personalized manner remain problematic in cancer treatment. Diagnosis tools for decision making are urgently needed in cancer patients. Results We set up a functional dynamic multiplexed immunophenotyping assay, measuring up to 50 parameters after 60 h of ex vivo stimulation with 12 immunomodulators. This flow cytometry- and Luminex-based assay was performed in 43 fresh tumors. We selected a 17 analyte-based immune reactivity score that detected primary resistance to PD-1 blockade. 26% of tumors exhibited both anergic tumor infiltrating lymphocytes (TILs) to rIL-2 and no responses to PD-1 blockade. The lack of CXCL10 release from fresh neoplasia was associated with primary resistance to PD-1 blockade. In seven cases amenable to in vivo therapy with PD-1 blockade, this “in sitro” assay anticipated the resistance to therapy in five tumors. 50% of primary resistance to PD-1 blockade could be shifted toward immunoreactivity using personalized combinatorial regimens. The presence of a specific regulatory T-cell subset correlated with anti-PD-1 antibody-induced immunosuppression that could be rescued by anti-killer inhibitory receptor mAbs. Impact Albeit exemplified in only 43 cases in this report, the in sitro assay has the power to predict primary resistance to PD-1 blockade and can propose a personalized combinatorial regimen of immunomodulators in 60 h based on freshly dissociated