J.J. Fournié
Therapeutic Innovations in B lymphomas
Our research project at a glance
Non-Hodgkin B cell lymphoma (NHL) including chronic lymphocytic leukemia (CLL) are increasingly frequent hematopoietic malignancies. Their treatment relies on chemotherapies, immunotherapies and radiotherapeutic combinations, but relapse and/or unresponsiveness are far too frequent. So our team aims at improving the efficacy of such treatments, notably by assessing newer immune checkpoint blockers (ICB) in this context.
Last update december 2019
Objectives
More specifically, we develop novel tools including analytic methods and biological models to find new molecular pathways for targeting NHL by novel drugs, and assess these in preclinical models, prior to translate the most promising ones in Phase l/ll clinical trials of IUC-Toulouse Oncopole.
This includes :
- predicting response of patients to treatment (ibrutinib in CLL, ICB in NHL, CAR-T cells in DLBCL),
- harnessing innate immunity against lymphoma models,
- development of a humanized anti-TAM mAb neutralizing the stromal support of NHL.
Last update december 2019
Key words
- Lymphoma
- MALC models
- OncoImmunology
- Datamining
- Bioinformatics
- Single cell RNAseq
- Therapy
- Immune checkpoints
- Flow cytometry
Last update december 2019
Labels and networks
Grants and funders
- Agence Nationale de la Recherche
- LYSARC
- Fondation ARC pour la recherche sur le cancer
- Ligue Nationale Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National de la Santé et de la Recherche Médicale
- Institut Claudius Regaud Centre de Lutte Contre le Cancer
- Région Occitanie Pyrénées – Méditerranée
- Fondation Janssen
- ImCORE Roche Genentech
Last update december 2019
Team members
Selected publications
2019 |
Pont, F; Tosolini, M; Fournié, JJ. Single-Cell Signature Explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets. Journal Article Nucleic Acids Res, 47 (21), pp. e133, 2019. @article{Pont2019, title = {Single-Cell Signature Explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets.}, author = {Pont, F. and Tosolini, M. and Fournié, JJ.}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868346/}, doi = {doi: 10.1093/nar/gkz601}, year = {2019}, date = {2019-12-02}, journal = {Nucleic Acids Res}, volume = {47}, number = {21}, pages = {e133}, abstract = {The momentum of scRNA-seq datasets prompts for simple and powerful tools exploring their meaningful signatures. Here we present Single-Cell_Signature_Explorer (https://sites.google.com/site/fredsoftwares/products/single-cell-signature-explorer), the first method for qualitative and high-throughput scoring of any gene set-based signature at the single cell level and its visualization using t-SNE or UMAP. By scanning datasets for single or combined signatures, it rapidly maps any multi-gene feature, exemplified here with signatures of cell lineages, biological hallmarks and metabolic pathways in large scRNAseq datasets of human PBMC, melanoma, lung cancer and adult testis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The momentum of scRNA-seq datasets prompts for simple and powerful tools exploring their meaningful signatures. Here we present Single-Cell_Signature_Explorer (https://sites.google.com/site/fredsoftwares/products/single-cell-signature-explorer), the first method for qualitative and high-throughput scoring of any gene set-based signature at the single cell level and its visualization using t-SNE or UMAP. By scanning datasets for single or combined signatures, it rapidly maps any multi-gene feature, exemplified here with signatures of cell lineages, biological hallmarks and metabolic pathways in large scRNAseq datasets of human PBMC, melanoma, lung cancer and adult testis. |
Curdy, N; Lanvin, O; Laurent, C; Fournié, JJ. ; DM., Franchini Regulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression. Journal Article Trends Cell Biol, 29 (10), pp. 777-790, 2019. @article{Curdy2019, title = {Regulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression.}, author = {Curdy, N. and Lanvin, O. and Laurent, C. and Fournié, JJ. and Franchini DM.}, url = {https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(19)30106-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0962892419301060%3Fshowall%3Dtrue}, doi = {doi: 10.1016/j.tcb.2019.07.002}, year = {2019}, date = {2019-10-01}, journal = {Trends Cell Biol}, volume = {29}, number = {10}, pages = {777-790}, abstract = {T cells responding to persistent tumor or viral antigens progressively lose their functional properties, a feature known as exhaustion. This state is also characterized by cell-surface expression of multiple inhibitory immune checkpoint receptors (IRs). Cancer immunotherapy by immune checkpoint targeting has shown impressive clinical outcomes, but requires substantial improvement given the limited number of patients who benefit from the treatment. Targeting the mechanisms controlling immune checkpoint expression could represent a step towards this aim. Accumulating data indicate that this strategy can limit immune checkpoint expression, in some instances simultaneously inhibiting several immune checkpoints. This review discusses various mechanisms through which IRs are activated or regulated, and ways these mechanisms could be exploited to develop more effective future immunotherapies.}, keywords = {}, pubstate = {published}, tppubtype = {article} } T cells responding to persistent tumor or viral antigens progressively lose their functional properties, a feature known as exhaustion. This state is also characterized by cell-surface expression of multiple inhibitory immune checkpoint receptors (IRs). Cancer immunotherapy by immune checkpoint targeting has shown impressive clinical outcomes, but requires substantial improvement given the limited number of patients who benefit from the treatment. Targeting the mechanisms controlling immune checkpoint expression could represent a step towards this aim. Accumulating data indicate that this strategy can limit immune checkpoint expression, in some instances simultaneously inhibiting several immune checkpoints. This review discusses various mechanisms through which IRs are activated or regulated, and ways these mechanisms could be exploited to develop more effective future immunotherapies. |
Laplagne, C; Domagala, M; Le-Naour, A; Quemerais, C; Hamel, D; Fournié, JJ. ; Couderc, B; Bousquet, C; Ferrand, A; Poupot, M Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression. Journal Article Int J Mol Sci, 20 (19), pp. E4719, 2019. @article{Laplagne2019, title = {Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression.}, author = {Laplagne, C. and Domagala, M. and Le-Naour, A. and Quemerais, C. and Hamel, D. and Fournié, JJ. and Couderc, B. and Bousquet, C. and Ferrand, A. and Poupot, M}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801830/}, doi = {10.3390/ijms20194719}, year = {2019}, date = {2019-09-23}, journal = {Int J Mol Sci}, volume = {20}, number = {19}, pages = {E4719}, abstract = {The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules. |
Decaup, E; Rossi, C; Gravelle, P; Laurent, C; Bordenave, J; Tosolini, M; Tourette, A; Perrial, E; Dumontet, C; Poupot, M; Klein, C; Savina, A; Fournié, JJ. ; Bezombes, C A Tridimensional Model for NK Cell-Mediated ADCC of Follicular Lymphoma. Journal Article Front Immunol, (10), pp. 1943, 2019. @article{Decaup2019, title = {A Tridimensional Model for NK Cell-Mediated ADCC of Follicular Lymphoma.}, author = {Decaup, E. and Rossi, C. and Gravelle, P. and Laurent, C. and Bordenave, J. and Tosolini, M. and Tourette, A. and Perrial, E. and Dumontet, C. and Poupot, M. and Klein, C. and Savina, A. and Fournié, JJ. and Bezombes, C}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702952/}, doi = { doi: 10.3389/fimmu.2019.01943. eCollection 2019.}, year = {2019}, date = {2019-08-14}, journal = {Front Immunol}, number = {10}, pages = {1943}, abstract = {Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation. |
Franchini, DM. ; Lanvin, O; Curdy, N; JJ., Fournié Control of lymphocyte activity by stress granules. New targets for immunotherapy ? Journal Article Med Sci, 35 (6-7), pp. 507-509, 2019. @article{Franchini2019b, title = {Control of lymphocyte activity by stress granules. New targets for immunotherapy ?}, author = {Franchini, DM. And Lanvin, O. and Curdy, N. and Fournié JJ.}, editor = {edp sciences}, url = {https://www.medecinesciences.org/fr/articles/medsci/abs/2019/07/msc190105/msc190105.html}, doi = {doi: 10.1051/medsci/2019109}, year = {2019}, date = {2019-07-05}, journal = {Med Sci}, volume = {35}, number = {6-7}, pages = {507-509}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Pizzolato, G; Kaminski, H; Tosolini, M; Franchini, DM. ; Pont, F; Martins, F; Valle, C; Labourdette, D; Cadot, S; Quillet-Mary, A; Poupot, M; Laurent, C; Ysebaert, L; Meraviglia, S; Dieli, F; Merville, P; Milpied, P; Déchanet-Merville, J; Fournié, JJ. Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes. Journal Article Proc natl Acad Sci USA, 116 (24), pp. 11906-11915, 2019. @article{Pizzolato2019, title = {Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes.}, author = {Pizzolato, G. and Kaminski, H. and Tosolini, M. and Franchini, DM. and Pont, F. and Martins, F. and Valle, C. and Labourdette, D. and Cadot, S. and Quillet-Mary, A. and Poupot, M. and Laurent, C. and Ysebaert, L. and Meraviglia, S. and Dieli, F. and Merville, P. and Milpied, P. and Déchanet-Merville, J. and Fournié, JJ.}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576116/}, doi = {doi: 10.1073/pnas.1818488116}, year = {2019}, date = {2019-06-11}, journal = {Proc natl Acad Sci USA}, volume = {116}, number = {24}, pages = {11906-11915}, abstract = {γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.}, keywords = {}, pubstate = {published}, tppubtype = {article} } γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV+ and CMV- donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions. |
Franchini, DM. ; Lanvin, O; Tosolini, M; Patras de, Campaigno E; Cammas, A; Péricart, S; Scarlata, CM. ; Lebras, M; Rossi, C; Ligat, L; Pont, F; Arimondo, PB. ; Laurent, C; Ayyoub, M; Despas, F; Lapeyre-Mestre, M; Millevoi, S; Fournié, JJ. Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells. Journal Article Cell rep, 26 (1), pp. 94-107, 2019. @article{Franchini2019, title = {Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells.}, author = {Franchini, DM. and Lanvin, O. and Tosolini, M. and Patras, de, Campaigno, E. and Cammas, A. and Péricart, S. and Scarlata, CM. and Lebras, M. and Rossi, C. and Ligat, L. and Pont, F. and Arimondo, PB. and Laurent, C. and Ayyoub, M. and Despas, F. and Lapeyre-Mestre, M. and Millevoi, S. and Fournié, JJ.}, editor = {Elsevier}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(18)31925-9}, doi = {doi: 10.1016/j.celrep.2018.12.014}, year = {2019}, date = {2019-01-02}, journal = {Cell rep}, volume = {26}, number = {1}, pages = {94-107}, abstract = {Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy. |
2018 |
Rossi, C; Gravelle, P; Decaup, E; Bordenave, J; Poupot, M; Tosolini, M1; Franchini, DM. ; Laurent, C; Morin, R; Lagarde, JM. ; Ysebaert, L; Ligat, L; Jean, C; Savina, A; Klein, C; Céspedes, AM. ; Perez-Galan, P; Fournié, JJ. ; Bezombes, C Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma. Journal Article Oncoimmunology, 8 (3), pp. 1554175, 2018. @article{Rossi2018, title = {Boosting γδ T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma.}, author = {Rossi, C. and Gravelle, P. and Decaup, E. and Bordenave, J. and Poupot, M. and Tosolini, M1. and Franchini, DM. and Laurent, C. and Morin, R. and Lagarde, JM. and Ysebaert, L. and Ligat, L. and Jean, C. and Savina, A. and Klein, C. and Céspedes, AM. and Perez-Galan, P. and Fournié, JJ. and Bezombes, C.}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350687/}, doi = {doi: 10.1080/2162402X.2018.1554175}, year = {2018}, date = {2018-12-17}, journal = {Oncoimmunology}, volume = {8}, number = {3}, pages = {1554175}, abstract = {Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes. In a 3D co-culture assay (MALC), γδ T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating γδ T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated γδ T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting γδ T cell anti-tumor functions in FL. |
Péricart, S; Tosolini, M; Gravelle, P; Rossi, C; Traverse-Glehen, A; Amara, N; Franchet, C; Martin, E; Bezombes, C; Laurent, G; Brousset, P; Fournié, JJ. ; Laurent, C Profiling Immune Escape in Hodgkin's and Diffuse large B-Cell Lymphomas Using the Transcriptome and Immunostaining. Journal Article Cancer (Basel), 10 (11), pp. 415, 2018. @article{Péricart2018, title = {Profiling Immune Escape in Hodgkin's and Diffuse large B-Cell Lymphomas Using the Transcriptome and Immunostaining.}, author = {Péricart, S. and Tosolini, M. and Gravelle, P. and Rossi, C. and Traverse-Glehen, A. and Amara, N. and Franchet, C. and Martin, E. and Bezombes, C. and Laurent, G. and Brousset, P. and Fournié, JJ. and Laurent, C.}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266061/}, doi = {doi: 10.3390/cancers10110415}, year = {2018}, date = {2018-10-31}, journal = {Cancer (Basel)}, volume = {10}, number = {11}, pages = {415}, abstract = {Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin's lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin's lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3⁺ and CD4⁺ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8⁺ T-cells, but HL had less CD68⁺CD163⁺ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin's lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin's lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3⁺ and CD4⁺ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8⁺ T-cells, but HL had less CD68⁺CD163⁺ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma. |
2017 |
Tosolini, M; Pont, F; Poupot, M; Vergez, F; Nicolau-Travers, ML. ; Vermijlen, D; Sarry, JE. ; Dieli, F; Fournié, JJ. Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays. Journal Article Oncoimmunology, 6 (3), pp. e1284723, 2017. @article{Tosolini2017, title = {Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays.}, author = {Tosolini, M. and Pont, F. and Poupot, M. and Vergez, F. and Nicolau-Travers, ML. and Vermijlen, D. and Sarry, JE. and Dieli, F. and Fournié, JJ.}, url = {https://www.tandfonline.com/doi/full/10.1080/2162402X.2017.1284723?scroll=top&needAccess=true}, doi = {doi: 10.1080/2162402X.2017.1284723}, year = {2017}, date = {2017-02-06}, journal = {Oncoimmunology}, volume = {6}, number = {3}, pages = {e1284723}, abstract = {Most human blood γδ cells are cytolytic TCRVγ9Vδ2+ lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2+ γδ lymphocytes and then applied this strategy to assess their abundance as tumor infiltrating lymphocytes (γδ TIL) in ∼10,000 cancer biopsies from 50 types of hematological and solid malignancies. We observed considerable inter-individual variation of TCRVγ9Vδ2+γδ TIL abundance both within each type and across the spectrum of cancers tested. We report their prominence in B cell-acute lymphoblastic leukemia (B-ALL), acute promyelocytic leukemia (M3-AML) and chronic myeloid leukemia (CML) as well as in inflammatory breast, prostate, esophagus, pancreas and lung carcinoma. Across all cancers, the abundance of αβ TILs and TCRVγ9Vδ2+ γδ TILs did not correlate. αβ TIL abundance paralleled the mutational load of tumors and positively correlated with inflammation, infiltration of monocytes, macrophages and dendritic cells (DC), antigen processing and presentation, and cytolytic activity, in line with an association with a favorable outcome. In contrast, the abundance of TCRVγ9Vδ2+ γδ TILs did not correlate with these hallmarks and was variably associated with outcome, suggesting that distinct contexts underlie TCRVγ9Vδ2+ γδ TIL and αβ TIL mobilizations in cancer.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Most human blood γδ cells are cytolytic TCRVγ9Vδ2+ lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2+ γδ lymphocytes and then applied this strategy to assess their abundance as tumor infiltrating lymphocytes (γδ TIL) in ∼10,000 cancer biopsies from 50 types of hematological and solid malignancies. We observed considerable inter-individual variation of TCRVγ9Vδ2+γδ TIL abundance both within each type and across the spectrum of cancers tested. We report their prominence in B cell-acute lymphoblastic leukemia (B-ALL), acute promyelocytic leukemia (M3-AML) and chronic myeloid leukemia (CML) as well as in inflammatory breast, prostate, esophagus, pancreas and lung carcinoma. Across all cancers, the abundance of αβ TILs and TCRVγ9Vδ2+ γδ TILs did not correlate. αβ TIL abundance paralleled the mutational load of tumors and positively correlated with inflammation, infiltration of monocytes, macrophages and dendritic cells (DC), antigen processing and presentation, and cytolytic activity, in line with an association with a favorable outcome. In contrast, the abundance of TCRVγ9Vδ2+ γδ TILs did not correlate with these hallmarks and was variably associated with outcome, suggesting that distinct contexts underlie TCRVγ9Vδ2+ γδ TIL and αβ TIL mobilizations in cancer. |
Boissard, F; Tosolini, M; Ligat, L; Quillet-Mary, A; Lopez, F; Fournie, J J; Ysebaert, L; Poupot, M Nurse-like cells promote CLL survival through LFA-3/CD2 interactions Journal Article Oncotarget, 8 (32), pp. 52225-52236, 2017, ISSN: 1949-2553 (Electronic) 1949-2553 (Linking). @article{RN1b, title = {Nurse-like cells promote CLL survival through LFA-3/CD2 interactions}, author = {Boissard, F. and Tosolini, M. and Ligat, L. and Quillet-Mary, A. and Lopez, F. and Fournie, J. J. and Ysebaert, L. and Poupot, M.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/28881725}, doi = {10.18632/oncotarget.13660}, issn = {1949-2553 (Electronic) 1949-2553 (Linking)}, year = {2017}, date = {2017-01-01}, journal = {Oncotarget}, volume = {8}, number = {32}, pages = {52225-52236}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2016 |
Betrian, S; Ysebaert, L; Heider, K H; Delord, J P; Fournie, J J; Quillet-Mary, A Blood Cancer J, 6 (11), pp. e496, 2016, ISSN: 2044-5385 (Electronic) 2044-5385 (Linking). @article{RN7b, title = {Idelalisib improves CD37 antibody BI 836826 cytotoxicity against chemo-resistant /relapse-initiating CLL cells: a rationale for combination treatment}, author = {Betrian, S. and Ysebaert, L. and Heider, K. H. and Delord, J. P. and Fournie, J. J. and Quillet-Mary, A.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27834943}, doi = {10.1038/bcj.2016.106}, issn = {2044-5385 (Electronic) 2044-5385 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {Blood Cancer J}, volume = {6}, number = {11}, pages = {e496}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Boissard, F; Laurent, C; Ramsay, A G; Quillet-Mary, A; Fournie, J J; Poupot, M; Ysebaert, L Nurse-like cells impact on disease progression in chronic lymphocytic leukemia Journal Article Blood Cancer J, 6 , pp. e381, 2016, ISSN: 2044-5385 (Electronic) 2044-5385 (Linking). @article{RN6b, title = {Nurse-like cells impact on disease progression in chronic lymphocytic leukemia}, author = {Boissard, F. and Laurent, C. and Ramsay, A. G. and Quillet-Mary, A. and Fournie, J. J. and Poupot, M. and Ysebaert, L.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26771807}, doi = {10.1038/bcj.2015.108}, issn = {2044-5385 (Electronic) 2044-5385 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {Blood Cancer J}, volume = {6}, pages = {e381}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Duault, C; Franchini, D M; Familliades, J; Cayrol, C; Roga, S; Girard, J P; Fournie, J J; Poupot, M TCRVgamma9 gammadelta T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism Journal Article J Immunol, 196 (1), pp. 493-502, 2016, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking). @article{RN5b, title = {TCRVgamma9 gammadelta T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism}, author = {Duault, C. and Franchini, D. M. and Familliades, J. and Cayrol, C. and Roga, S. and Girard, J. P. and Fournie, J. J. and Poupot, M.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26608919}, doi = {10.4049/jimmunol.1500260}, issn = {1550-6606 (Electronic) 0022-1767 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {J Immunol}, volume = {196}, number = {1}, pages = {493-502}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Guggino, G; Ciccia, F; Di Liberto, D; Lo Pizzo, M; Ruscitti, P; Cipriani, P; Ferrante, A; Sireci, G; Dieli, F; Fournie, J J; Giacomelli, R; Triolo, G Interleukin (IL)-9/IL-9R axis drives gammadelta T cells activation in psoriatic arthritis patients Journal Article Clin Exp Immunol, 186 (3), pp. 277-283, 2016, ISSN: 1365-2249 (Electronic) 0009-9104 (Linking). @article{RN4b, title = {Interleukin (IL)-9/IL-9R axis drives gammadelta T cells activation in psoriatic arthritis patients}, author = {Guggino, G. and Ciccia, F. and Di Liberto, D. and Lo Pizzo, M. and Ruscitti, P. and Cipriani, P. and Ferrante, A. and Sireci, G. and Dieli, F. and Fournie, J. J. and Giacomelli, R. and Triolo, G.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27543964}, doi = {10.1111/cei.12853}, issn = {1365-2249 (Electronic) 0009-9104 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {Clin Exp Immunol}, volume = {186}, number = {3}, pages = {277-283}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Poupot, M; Turrin, C O; Caminade, A M; Fournie, J J; Attal, M; Poupot, R; Fruchon, S Nanomedicine, 12 (8), pp. 2321-2330, 2016, ISSN: 1549-9642 (Electronic) 1549-9634 (Linking). @article{RN3b, title = {Poly(phosphorhydrazone) dendrimers: yin and yang of monocyte activation for human NK cell amplification applied to immunotherapy against multiple myeloma}, author = {Poupot, M. and Turrin, C. O. and Caminade, A. M. and Fournie, J. J. and Attal, M. and Poupot, R. and Fruchon, S.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27498187}, doi = {10.1016/j.nano.2016.07.009}, issn = {1549-9642 (Electronic) 1549-9634 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {Nanomedicine}, volume = {12}, number = {8}, pages = {2321-2330}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Tosolini, M; Algans, C; Pont, F; Ycart, B; Fournie, J J Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas Journal Article Oncoimmunology, 5 (7), pp. e1188246, 2016, ISSN: 2162-4011 (Print) 2162-4011 (Linking). @article{RN2b, title = {Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas}, author = {Tosolini, M. and Algans, C. and Pont, F. and Ycart, B. and Fournie, J. J.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/27622044}, doi = {10.1080/2162402X.2016.1188246}, issn = {2162-4011 (Print) 2162-4011 (Linking)}, year = {2016}, date = {2016-01-01}, journal = {Oncoimmunology}, volume = {5}, number = {7}, pages = {e1188246}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2015 |
Lafouresse, F; Bellard, E; Laurent, C; Moussion, C; Fournie, J J; Ysebaert, L; Girard, J P L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo Journal Article Blood, 126 (11), pp. 1336-45, 2015, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking). @article{RN8b, title = {L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo}, author = {Lafouresse, F. and Bellard, E. and Laurent, C. and Moussion, C. and Fournie, J. J. and Ysebaert, L. and Girard, J. P.}, url = {https://www.ncbi.nlm.nih.gov/pubmed/26162407}, doi = {10.1182/blood-2015-02-626291}, issn = {1528-0020 (Electronic) 0006-4971 (Linking)}, year = {2015}, date = {2015-01-01}, journal = {Blood}, volume = {126}, number = {11}, pages = {1336-45}, keywords = {}, pubstate = {published}, tppubtype = {article} } |