Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Global Analysis of Molecular Connections at FL Synapse
2.2. Activation of Tfh Cells in FL Tumor
2.3. Impaired Response of FL B Cells to IFN-γ
2.4. The FL Microenvironment Improves the Adhesion of B Cells to Stromal Cells
2.5. Enhanced CD200 Expression in FL Sustains a Tolerogenic Niche
3. Discussion
4. Materials and Methods
4.1. Patient Samples
4.2. Preparation of Highly Purified Cells
4.3. Gene Expression Profiling
4.4. Tools for Affymetrix Dataset Analysis
4.5. Supplementary Method for GEP Analysis
4.6. Quantitative RT-PCR
4.7. Flow Cytometry Analysis
4.8. Primary B or T Lymphocyte Culture
4.9. Dendritic Cell Production and Culture
4.10. Indoleamine 2,3-Dioxygenase (IDO) Activity Analysis
4.11. Adhesion Assay
4.12. Statistical and Bioinformatic Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Mesin, L.; Ersching, J.; Victora, G.D. Germinal Center B Cell Dynamics. Immunity 2016, 45, 471–482. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cyster, J.G.; Allen, C.D.C. B Cell Responses: Cell Interaction Dynamics and Decisions. Cell 2019, 177, 524–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mayer, C.T.; Gazumyan, A.; Kara, E.E.; Gitlin, A.D.; Golijanin, J.; Viant, C.; Pai, J.; Oliveira, T.Y.; Wang, Q.; Escolano, A.; et al. The microanatomic segregation of selection by apoptosis in the germinal center. Science 2017, 358, eaao2602. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roulland, S.; Faroudi, M.; Mamessier, E.; Sungalee, S.; Salles, G.; Nadel, B. Early Steps of Follicular Lymphoma Pathogenesis. In Advances in Immunology; Elsevier: Amsterdam, The Netherlands, 2011; Volume 111, pp. 1–46. ISBN 978-0-12-385991-4. [Google Scholar]
- Green, M.R. Chromatin modifying gene mutations in follicular lymphoma. Blood 2018, 131, 595–604. [Google Scholar] [CrossRef]
- Pasqualucci, L. Molecular pathogenesis of germinal center-derived B cell lymphomas. Immunol. Rev. 2019, 288, 240–261. [Google Scholar] [CrossRef]
- Okosun, J.; Bödör, C.; Wang, J.; Araf, S.; Yang, C.-Y.; Pan, C.; Boller, S.; Cittaro, D.; Bozek, M.; Iqbal, S.; et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 2014, 46, 176–181. [Google Scholar] [CrossRef]
- Desmots, F.; Roussel, M.; Pangault, C.; Llamas-Gutierrez, F.; Pastoret, C.; Guiheneuf, E.; Le Priol, J.; Camara-Clayette, V.; Caron, G.; Henry, C.; et al. Pan-HDAC Inhibitors Restore PRDM1 Response to IL21 in CREBBP-Mutated Follicular Lymphoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 735–746. [Google Scholar] [CrossRef] [Green Version]
- Milpied, P.; Cervera-Marzal, I.; Mollichella, M.-L.; Tesson, B.; Brisou, G.; Traverse-Glehen, A.; Salles, G.; Spinelli, L.; Nadel, B. Human germinal center transcriptional programs are de-synchronized in B cell lymphoma. Nat. Immunol. 2018, 19, 1013. [Google Scholar] [CrossRef]
- Araf, S.; Wang, J.; Korfi, K.; Pangault, C.; Kotsiou, E.; Rio-Machin, A.; Rahim, T.; Heward, J.; Clear, A.; Iqbal, S.; et al. Genomic profiling reveals spatial intra-tumor heterogeneity in follicular lymphoma. Leukemia 2018, 32, 1261–1265. [Google Scholar] [CrossRef] [Green Version]
- Amin, R.; Mourcin, F.; Uhel, F.; Pangault, C.; Ruminy, P.; Dupré, L.; Guirriec, M.; Marchand, T.; Fest, T.; Lamy, T.; et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood 2015, 126, 1911–1920. [Google Scholar] [CrossRef] [Green Version]
- Amé-Thomas, P.; Tarte, K. The yin and the yang of follicular lymphoma cell niches: Role of microenvironment heterogeneity and plasticity. Semin. Cancer Biol. 2014, 24, 23–32. [Google Scholar] [CrossRef] [PubMed]
- Lamaison, C.; Tarte, K. Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy. Immunol. Lett. 2019, 215, 12–18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dave, S.S.; Wright, G.; Tan, B.; Rosenwald, A.; Gascoyne, R.D.; Chan, W.C.; Fisher, R.I.; Braziel, R.M.; Rimsza, L.M.; Grogan, T.M.; et al. Prediction of Survival in Follicular Lymphoma Based on Molecular Features of Tumor-Infiltrating Immune Cells. N. Engl. J. Med. 2004, 351, 2159–2169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wahlin, B.E.; Sander, B.; Christensson, B.; Ostenstad, B.; Holte, H.; Brown, P.D.; Sundström, C.; Kimby, E. Entourage: The immune microenvironment following follicular lymphoma. Blood Cancer J. 2012, 2, e52. [Google Scholar] [CrossRef] [PubMed]
- Pandey, S.; Mourcin, F.; Marchand, T.; Nayar, S.; Guirriec, M.; Pangault, C.; Monvoisin, C.; Amé-Thomas, P.; Guilloton, F.; Dulong, J.; et al. IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma. Blood 2017, 129, 2507–2518. [Google Scholar] [CrossRef] [Green Version]
- Pangault, C.; Amé-Thomas, P.; Ruminy, P.; Rossille, D.; Caron, G.; Baia, M.; De Vos, J.; Roussel, M.; Monvoisin, C.; Lamy, T.; et al. Follicular lymphoma cell niche: Identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 2010, 24, 2080–2089. [Google Scholar] [CrossRef]
- Amé-Thomas, P.; Le Priol, J.; Yssel, H.; Caron, G.; Pangault, C.; Jean, R.; Martin, N.; Marafioti, T.; Gaulard, P.; Lamy, T.; et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma: Role in the survival of malignant B cells. Leukemia 2012, 26, 1053–1063. [Google Scholar] [CrossRef] [Green Version]
- Guilloton, F.; Caron, G.; Ménard, C.; Pangault, C.; Amé-Thomas, P.; Dulong, J.; De Vos, J.; Rossille, D.; Henry, C.; Lamy, T.; et al. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes. Blood 2012, 119, 2556–2567. [Google Scholar] [CrossRef] [Green Version]
- Barclay, A.N.; Wright, G.J.; Brooke, G.; Brown, M.H. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 2002, 23, 285–290. [Google Scholar] [CrossRef]
- Amé-Thomas, P.; Hoeller, S.; Artchounin, C.; Misiak, J.; Braza, M.S.; Jean, R.; Le Priol, J.; Monvoisin, C.; Martin, N.; Gaulard, P.; et al. CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells. Blood 2015, 125, 2381–2385. [Google Scholar] [CrossRef] [Green Version]
- Bangs, S.C.; Baban, D.; Cattan, H.J.; Li, C.K.-F.; McMichael, A.J.; Xu, X.-N. Human CD4+ memory T cells are preferential targets for bystander activation and apoptosis. J. Immunol. Baltim. Md 1950 2009, 182, 1962–1971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Crotty, S. T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity 2019, 50, 1132–1148. [Google Scholar] [CrossRef] [PubMed]
- Chavele, K.-M.; Merry, E.; Ehrenstein, M.R. Cutting edge: Circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production. J. Immunol. Baltim. Md 1950 2015, 194, 2482–2485. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Papillion, A.; Powell, M.D.; Chisolm, D.A.; Bachus, H.; Fuller, M.J.; Weinmann, A.S.; Villarino, A.; O’Shea, J.J.; León, B.; Oestreich, K.J.; et al. Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells. Sci. Immunol. 2019, 4, eaaw7636. [Google Scholar] [CrossRef] [PubMed]
- McDonald, P.W.; Read, K.A.; Baker, C.E.; Anderson, A.E.; Powell, M.D.; Ballesteros-Tato, A.; Oestreich, K.J. IL-7 signalling represses Bcl-6 and the TFH gene program. Nat. Commun. 2016, 7. [Google Scholar] [CrossRef]
- Xu, H.; Li, X.; Liu, D.; Li, J.; Zhang, X.; Chen, X.; Hou, S.; Peng, L.; Xu, C.; Liu, W.; et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature 2013, 496, 523–527. [Google Scholar] [CrossRef]
- Green, M.R.; Kihira, S.; Liu, C.L.; Nair, R.V.; Salari, R.; Gentles, A.J.; Irish, J.; Stehr, H.; Vicente-Dueñas, C.; Romero-Camarero, I.; et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc. Natl. Acad. Sci. USA 2015, 112, E1116–E1125. [Google Scholar] [CrossRef] [Green Version]
- Wilson, M.R.; Zoubeidi, A. Clusterin as a therapeutic target. Expert Opin. Ther. Targets 2017, 21, 201–213. [Google Scholar] [CrossRef]
- Afanasyeva, M.A.; Britanova, L.V.; Korneev, K.V.; Mitkin, N.A.; Kuchmiy, A.A.; Kuprash, D.V. Clusterin Is a Potential Lymphotoxin Beta Receptor Target That Is Upregulated and Accumulates in Germinal Centers of Mouse Spleen during Immune Response. PLoS ONE 2014, 9, e98349. [Google Scholar] [CrossRef] [Green Version]
- Moreaux, J.; Veyrune, J.L.; Reme, T.; De Vos, J.; Klein, B. CD200: A putative therapeutic target in cancer. Biochem. Biophys. Res. Commun. 2008, 366, 117–122. [Google Scholar] [CrossRef] [Green Version]
- Munn, D.H.; Mellor, A.L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Investig. 2007, 117, 1147–1154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schmidt, S.V.; Nino-Castro, A.C.; Schultze, J.L. Regulatory dendritic cells: There is more than just immune activation. Front. Immunol. 2012, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schluns, K.S.; Kieper, W.C.; Jameson, S.C.; Lefrançois, L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat. Immunol. 2000, 1, 426–432. [Google Scholar] [CrossRef] [PubMed]
- Carrette, F.; Surh, C.D. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin. Immunol. 2012, 24, 209–217. [Google Scholar] [CrossRef] [Green Version]
- Horn, F.; Henze, C.; Heidrich, K. Interleukin-6 signal transduction and lymphocyte function. Immunobiology 2000, 202, 151–167. [Google Scholar] [CrossRef]
- Seo, Y.B.; Im, S.J.; Namkoong, H.; Kim, S.W.; Choi, Y.W.; Kang, M.C.; Lim, H.S.; Jin, H.T.; Yang, S.H.; Cho, M.L.; et al. Crucial roles of interleukin-7 in the development of T follicular helper cells and in the induction of humoral immunity. J. Virol. 2014, 88, 8998–9009. [Google Scholar] [CrossRef] [Green Version]
- Hale, J.S.; Ahmed, R. Memory T Follicular Helper CD4 T Cells. Front. Immunol. 2015, 6. [Google Scholar] [CrossRef] [Green Version]
- Fielding, C.A.; Jones, G.W.; McLoughlin, R.M.; McLeod, L.; Hammond, V.J.; Uceda, J.; Williams, A.S.; Lambie, M.; Foster, T.L.; Liao, C.-T.; et al. Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation. Immunity 2014, 40, 40–50. [Google Scholar] [CrossRef] [Green Version]
- Hoek, R.M. Down-Regulation of the Macrophage Lineage Through Interaction with OX2 (CD200). Science 2000, 290, 1768–1771. [Google Scholar] [CrossRef]
- Jenmalm, M.C.; Cherwinski, H.; Bowman, E.P.; Phillips, J.H.; Sedgwick, J.D. Regulation of Myeloid Cell Function through the CD200 Receptor. J. Immunol. 2006, 176, 191–199. [Google Scholar] [CrossRef]
- Yu, K.; Chen, Z.; Gorczynski, R. Effect of CD200 and CD200R1 expression within tissue grafts on increased graft survival in allogeneic recipients. Immunol. Lett. 2013, 149, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Liu, J.-Q.; Talebian, F.; El-Omrani, H.Y.; Khattabi, M.; Yu, L.; Bai, X.-F. Tumor expression of CD200 inhibits IL-10 production by tumor-associated myeloid cells and prevents tumor immune evasion of CTL therapy. Eur. J. Immunol. 2010, 40, 2569–2579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dorfman, D.M.; Shahsafaei, A. CD200 (OX-2 membrane glycoprotein) is expressed by follicular T helper cells and in angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 2011, 35, 76–83. [Google Scholar] [CrossRef] [PubMed]
- Douds, J.J.; Long, D.J.; Kim, A.S.; Li, S. Diagnostic and prognostic significance of CD200 expression and its stability in plasma cell myeloma. J. Clin. Pathol. 2014, 67, 792–796. [Google Scholar] [CrossRef]
- Epron, G.; Ame-Thomas, P.; Le Priol, J.; Pangault, C.; Dulong, J.; Lamy, T.; Fest, T.; Tarte, K. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: Role of IL-15 and CD40L signaling. Leukemia 2012, 26, 139–148. [Google Scholar] [CrossRef] [Green Version]
- Chevalier, N.; Mueller, M.; Mougiakakos, D.; Ihorst, G.; Marks, R.; Schmitt-Graeff, A.; Veelken, H. Analysis of dendritic cell subpopulations in follicular lymphoma with respect to the tumor immune microenvironment. Leuk. Lymphoma 2016, 57, 2150–2160. [Google Scholar] [CrossRef]
- Najar, M.; Raicevic, G.; Jebbawi, F.; De Bruyn, C.; Meuleman, N.; Bron, D.; Toungouz, M.; Lagneaux, L. Characterization and functionality of the CD200–CD200R system during mesenchymal stromal cell interactions with T-lymphocytes. Immunol. Lett. 2012, 146, 50–56. [Google Scholar] [CrossRef]
- Ninomiya, S.; Hara, T.; Tsurumi, H.; Hoshi, M.; Kanemura, N.; Goto, N.; Kasahara, S.; Shimizu, M.; Ito, H.; Saito, K.; et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann. Hematol. 2011, 90, 409–416. [Google Scholar] [CrossRef]
- Frazzi, R.; Casali, B.; Iori, M.; Nicoli, D.; Mammi, C.; Merli, F. Increase in clusterin forms part of the stress response in Hodgkin’s lymphoma. Int. J. Oncol. 2011, 38, 677–684. [Google Scholar] [CrossRef]
- Yu, B.; Yang, Y.; Liu, H.; Gong, M.; Millard, R.W.; Wang, Y.-G.; Ashraf, M.; Xu, M. Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. PLoS ONE 2016, 11, e0151542. [Google Scholar] [CrossRef]
- Murai, T. Lipid Raft-Mediated Regulation of Hyaluronan–CD44 Interactions in Inflammation and Cancer. Front. Immunol. 2015, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clark, R.A.; Alon, R.; Springer, T.A. CD44 and hyaluronan-dependent rolling interactions of lymphocytes on tonsillar stroma. J. Cell Biol. 1996, 134, 1075–1087. [Google Scholar] [CrossRef] [PubMed]
- Kryworuchko, M.; Diaz-Mitoma, F.; Kumar, A. Interferon-γ Inhibits CD44–Hyaluronan Interactions in Normal Human B Lymphocytes. Exp. Cell Res. 1999, 250, 241–252. [Google Scholar] [CrossRef] [PubMed]
- Detry, G.; Drénou, B.; Ferrant, A.; Theate, I.; Michaux, L.; Scheiff, J.M.; Latinne, D.; Leveugle, P.; Mazzon, A.M.; Deneys, V. Tracking the follicular lymphoma cells in flow cytometry: Characterisation of a new useful antibody combination. Eur. J. Haematol. 2004, 73, 325–331. [Google Scholar] [CrossRef]
- Misiak, J.; Tarte, K.; Amé-Thomas, P. Flow Cytometric Detection and Isolation of Human Tonsil or Lymph Node T Follicular Helper Cells. In T Follicular Helper Cells; Espéli, M., Linterman, M., Eds.; Springer: New York, NY, USA, 2015; Volume 1291, pp. 163–173. ISBN 978-1-4939-2497-4. [Google Scholar]
- Irizarry, R.A. From CEL Files to Annotated Lists of Interesting Genes. In Bioinformatics and Computational Biology Solutions Using R and Bioconductor; Gentleman, R., Carey, V.J., Huber, W., Irizarry, R.A., Dudoit, S., Eds.; Springer: New York, NY, USA, 2005; pp. 431–442. ISBN 978-0-387-25146-2. [Google Scholar]
- Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 2005, 102, 15545–15550. [Google Scholar] [CrossRef] [Green Version]
- Kuleshov, M.V.; Jones, M.R.; Rouillard, A.D.; Fernandez, N.F.; Duan, Q.; Wang, Z.; Koplev, S.; Jenkins, S.L.; Jagodnik, K.M.; Lachmann, A.; et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016, 44, W90–W97. [Google Scholar] [CrossRef] [Green Version]
- Schaefer, C.F.; Anthony, K.; Krupa, S.; Buchoff, J.; Day, M.; Hannay, T.; Buetow, K.H. PID: The Pathway Interaction Database. Nucleic Acids Res. 2009, 37, D674–D679. [Google Scholar] [CrossRef]
- Mi, H.; Muruganujan, A.; Thomas, P.D. PANTHER in 2013: Modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res. 2012, 41, D377–D386. [Google Scholar] [CrossRef] [Green Version]
Non-Malignant Patient Derived Cells | FL-Derived Cells | |
---|---|---|
B lymphocytes | 7 tonsils from children | 10 FL lymph nodes |
Tfh lymphocytes | 7 tonsils from children | 7 FL lymph nodes |
Mesenchymal stromal cells | 8 HD bone marrow | 8 FL bone marrow |
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Pangault, C.; Amé-Thomas, P.; Rossille, D.; Dulong, J.; Caron, G.; Nonn, C.; Chatonnet, F.; Desmots, F.; Launay, V.; Lamy, T.; et al. Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse. Cancers 2020, 12, 2865. https://doi.org/10.3390/cancers12102865
Pangault C, Amé-Thomas P, Rossille D, Dulong J, Caron G, Nonn C, Chatonnet F, Desmots F, Launay V, Lamy T, et al. Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse. Cancers. 2020; 12(10):2865. https://doi.org/10.3390/cancers12102865
Chicago/Turabian StylePangault, Céline, Patricia Amé-Thomas, Delphine Rossille, Joëlle Dulong, Gersende Caron, Céline Nonn, Fabrice Chatonnet, Fabienne Desmots, Vincent Launay, Thierry Lamy, and et al. 2020. "Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse" Cancers 12, no. 10: 2865. https://doi.org/10.3390/cancers12102865
APA StylePangault, C., Amé-Thomas, P., Rossille, D., Dulong, J., Caron, G., Nonn, C., Chatonnet, F., Desmots, F., Launay, V., Lamy, T., Fest, T., & Tarte, K. (2020). Integrative Analysis of Cell Crosstalk within Follicular Lymphoma Cell Niche: Towards a Definition of the FL Supportive Synapse. Cancers, 12(10), 2865. https://doi.org/10.3390/cancers12102865