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1. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas

Author

Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena, and Eliane Piaggio

Subjects
Science
Abstract

Abstract Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.

Published
2022
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2. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients

Author

Nicolas Gonzalo Núñez, Jimena Tosello Boari, Rodrigo Nalio Ramos, Wilfrid Richer, Nicolas Cagnard, Cyrill Dimitri Anderfuhren, Leticia Laura Niborski, Jeremy Bigot, Didier Meseure, Philippe De La Rochere, Maud Milder, Sophie Viel, Delphine Loirat, Louis Pérol, Anne Vincent-Salomon, Xavier Sastre-Garau, Becher Burkhard, Christine Sedlik, Olivier Lantz, Sebastian Amigorena, and Eliane Piaggio

Subjects
Science
Abstract

Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.

Published
2020
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3. Author Correction: CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas

Author

Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena, and Eliane Piaggio

Subjects
Science
Published
2023
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4. Data from IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues Antitumor NK Cell Function by Regulatory T-cell Modulation

Author

Eliane Piaggio, Christine Sedlik, Olivier Lantz, Leticia Laura Niborski, Ruby Alonso, Jordan Denizeau, Anaïs Pinto, Philippe De La Rochere, Nicolas Gonzalo Núñez, and Pamela Caudana

Abstract

High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx), which redirect IL2 action to CD8+ T and natural killer (NK) cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti–PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance. Both combinations work by reinvigorating exhausted intratumoral CD8+ T cells and by increasing the breadth of tumor-specific T-cell responses. However, only the IL2Cx/anti–CTLA-4 combination is able to rescue NK cell antitumor function by modulating intratumoral regulatory T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving the way for the rational design of combinatorial antitumor therapies.

Published
2023
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6. IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues Antitumor NK Cell Function by Regulatory T-cell Modulation

Author

Philippe De La Rochere, Ruby Alonso, Olivier Lantz, Pamela Caudana, Anaïs Pinto, Nicolás Gonzalo Núñez, Jordan Denizeau, Eliane Piaggio, Christine Sedlik, and Leticia Laura Niborski

Subjects
0301 basic medicine, Cancer Research, Regulatory T cell, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, Cell, chemical and pharmacologic phenomena, Antigen-Antibody Complex, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Cell Line, Tumor, Tumor Microenvironment, medicine, Animals, CTLA-4 Antigen, Chemistry, Antibodies, Monoclonal, hemic and immune systems, Neoplasms, Experimental, Immunotherapy, Mice, Mutant Strains, Blockade, Killer Cells, Natural, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Drug Resistance, Neoplasm, Cell culture, CTLA-4, 030220 oncology & carcinogenesis, Cancer research, Interleukin-2, Female, CD8, T-Lymphocytes, Cytotoxic
Abstract

High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx), which redirect IL2 action to CD8+ T and natural killer (NK) cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti–PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance. Both combinations work by reinvigorating exhausted intratumoral CD8+ T cells and by increasing the breadth of tumor-specific T-cell responses. However, only the IL2Cx/anti–CTLA-4 combination is able to rescue NK cell antitumor function by modulating intratumoral regulatory T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving the way for the rational design of combinatorial antitumor therapies.

Published
2019
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7. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients

Author

Anne Vincent-Salomon, Becher Burkhard, Delphine Loirat, Cyrill Dimitri Anderfuhren, Nicolas Cagnard, Jimena Tosello Boari, Wilfrid Richer, Christine Sedlik, Sophie Viel, Olivier Lantz, Louis Pérol, Xavier Sastre-Garau, Sebastian Amigorena, Nicolás Gonzalo Núñez, Didier Meseure, Rodrigo Nalio Ramos, Eliane Piaggio, Maud Milder, Philippe De La Rochere, Leticia Laura Niborski, Jeremy Bigot, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), Bioinformatics Platform [Paris], Université Paris Descartes - Paris 5 (UPD5), Département de Biologie des Tumeurs, Institut Curie [Paris], Centre d'Investigation Clinique Biothérapie [Paris] (CICBT), Département d'Oncologie Médicale [Paris], Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Department of Biopathology [Vandoeuvre-lès-Nancy], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER-UNICANCER, This work was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche sur le Cancer (ARC), the Institut Curie, the Agence Nationale pour la Recherche (ANR Emergence program), the Institut National du Cancer (INCa), IGR-Curie 1428 Clinical Investigation Center, Labex DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX0043), SIRIC (INCa-DGOS-Inserm_12554, projets 2011–2017:INCa-DGOS-Inserm_4654). N.G.N. received a fellowship from Ligue Nationale Contre le Cancer and the University Research Priority Program (URPP)., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Bodescot, Myriam, and Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, medicine.medical_treatment, General Physics and Astronomy, Cancer immunotherapy, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, T-Lymphocytes, Regulatory, Article, General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, lcsh:Science, Lymph node, Immunosuppression Therapy, Multidisciplinary, business.industry, T-cell receptor, Immunosuppression, hemic and immune systems, General Chemistry, medicine.disease, 3. Good health, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030104 developmental biology, medicine.anatomical_structure, Lymphatic Metastasis, 030220 oncology & carcinogenesis, B7-1 Antigen, Cancer research, Tumour immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:Q, Lymph Nodes, Lymph, business, CD80
Abstract

Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy., Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.

Published
2020
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8. Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Author

Sonia Lameiras, Pamela Caudana, Sylvain Baulande, Arnault Tauziède-Espariat, Nicolas Servant, Franck Bourdeaut, Amaury Leruste, Joshua J. Waterfall, Didier Surdez, Mamy Andrianteranagna, Stéphanie Puget, Sandrine Grossetête-Lalami, Eliane Piaggio, Christine Sedlik, Jimena Tosello, Mylène Bohec, Philippe Benaroch, Rodrigo Nalio Ramos, Celio Pouponnot, Jovan Nikolic, Julie Helft, Solene Brohard, Valeria Manriquez, Louise Galmiche, Leticia Laura Niborski, Olivier Delattre, Aurore Coulomb, Zhi-Yan Han, Céline Chauvin, Kevin Beccaria, Julien Masliah-Planchon, Wilfrid Richer, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris sciences et lettres (PSL), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathology Department [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Gene and Cell Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Immunité et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, This work was funded by the BMS and the Janssen Horizon Foundations, the Société Française des Cancers de l’Enfant (SFCE) with the associations 'Enfants et Santé' and 'L’Étoile de Martin,' INCA PL-BIO 2016 call for Project from the French Minister of Research, the 'Abigael,' 'ADAM,' 'Au Nom d’Andréa,' and 'Marabout de Ficelles' associations. RTOP team is supported by the SiRIC-Curie Program (grant INCa-DGOS-4654). INSERM U830 is supported by the Institut National de la Santé et de la Recherche Médicale, Curie Institute and the Ligue Nationale Contre Le Cancer. TransImm team is supported by the SiRIC-Curie Program (grant INCa-DGOS-12554), the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), and the Center of Clinical Investigation (CIC IGR-Curie 1428). A.L. and P.C. were supported by the PhD program of Curie Institute., The authors thank S. Cairo, M. Chicard, J. Denizeau, C. Goudot, P. Gueguen, I. Jimenez, N. Manel, A. Pinto, S. Viel, S. Zaidi, and the mouse and the cytometry facility cores at Curie Institute., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), PSL Research University (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], SMARCB1, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, single-cell RNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Immune system, endogenous retrovirus, medicine, Animals, Humans, tumor immunology, AT/RT, rhabdoid tumor, Immunogenicity, T-cell receptor, Nuclear Proteins, Cell Biology, Immunotherapy, Chromatin Assembly and Disassembly, Pediatric cancer, Immunohistochemistry, SWI/SNF, 3. Good health, Chromatin, pediatric cancer, DNA-Binding Proteins, Mice, Inbred C57BL, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, immunotherapy, T cell receptor, CD8, Transcription Factors
Abstract

International audience; Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.

Published
2019
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