Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

Adrian Gottschlich; Ruth Grünmeier; Gordon Victor Hoffmann; Sayantan Nandi; Vladyslav Kavaka; Philipp Jie Müller; Jakob Jobst; Arman Oner; Rainer Kaiser; Jan Gärtig; Ignazio Piseddu; Stephanie Frenz-Wiessner; Savannah D. Fairley; Heiko Schulz; Veronika Igl; Thomas Alexander Janert; Lea Di Fina; Maité Mulkers; Moritz Thomas; Daria Briukhovetska; Donjetë Simnica; Emanuele Carlini; Christina Angeliki Tsiverioti; Marcel P. Trefny; Theo Lorenzini; Florian Märkl; Pedro Mesquita; Ruben Brabenec; Thaddäus Strzalkowski; Sophia Stock; Stefanos Michaelides; Johannes Hellmuth; Martin Thelen; Sarah Reinke; Wolfram Klapper; Pascal Francois Gelebart; Leo Nicolai; Carsten Marr; Eduardo Beltrán; Remco T.A. Megens; Christoph Klein; Fanny Baran-Marszak; Andreas Rosenwald; Michael von Bergwelt-Baildon; Paul J. Bröckelmann; Stefan Endres; Sebastian Kobold

doi:10.1182/blood.2023022197

Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

Adrian Gottschlich^*, Ruth Grünmeier, Gordon Victor Hoffmann, Sayantan Nandi, Vladyslav Kavaka, Philipp Jie Müller, Jakob Jobst, Arman Oner, Rainer Kaiser, Jan Gärtig, Ignazio Piseddu, Stephanie Frenz-Wiessner, Savannah D. Fairley, Heiko Schulz, Veronika Igl, Thomas Alexander Janert, Lea Di Fina, Maité Mulkers, Moritz Thomas, Daria BriukhovetskaDonjetë Simnica, Emanuele Carlini, Christina Angeliki Tsiverioti, Marcel P. Trefny, Theo Lorenzini, Florian Märkl, Pedro Mesquita, Ruben Brabenec, Thaddäus Strzalkowski, Sophia Stock, Stefanos Michaelides, Johannes Hellmuth, Martin Thelen, Sarah Reinke, Wolfram Klapper, Pascal Francois Gelebart, Leo Nicolai, Carsten Marr, Eduardo Beltrán, Remco T.A. Megens, Christoph Klein, Fanny Baran-Marszak, Andreas Rosenwald, Michael von Bergwelt-Baildon, Paul J. Bröckelmann, Stefan Endres, Sebastian Kobold^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell–based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86–CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

Original language	English
Journal	Blood
DOIs	https://doi.org/10.1182/blood.2023022197
Publication status	E-pub ahead of print - Dec 2024

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10.1182/blood.2023022197

Cite this

Gottschlich, A., Grünmeier, R., Hoffmann, G. V., Nandi, S., Kavaka, V., Müller, P. J., Jobst, J., Oner, A., Kaiser, R., Gärtig, J., Piseddu, I., Frenz-Wiessner, S., Fairley, S. D., Schulz, H., Igl, V., Janert, T. A., Di Fina, L., Mulkers, M., Thomas, M., ... Kobold, S. (2024). Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma. Blood. Advance online publication. https://doi.org/10.1182/blood.2023022197

@article{ca19d24d97d844d79ebbd0c809d45df8,

title = "Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma",

abstract = "The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell–based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86–CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.",

author = "Adrian Gottschlich and Ruth Gr{\"u}nmeier and Hoffmann, {Gordon Victor} and Sayantan Nandi and Vladyslav Kavaka and M{\"u}ller, {Philipp Jie} and Jakob Jobst and Arman Oner and Rainer Kaiser and Jan G{\"a}rtig and Ignazio Piseddu and Stephanie Frenz-Wiessner and Fairley, {Savannah D.} and Heiko Schulz and Veronika Igl and Janert, {Thomas Alexander} and {Di Fina}, Lea and Mait{\'e} Mulkers and Moritz Thomas and Daria Briukhovetska and Donjet{\"e} Simnica and Emanuele Carlini and Tsiverioti, {Christina Angeliki} and Trefny, {Marcel P.} and Theo Lorenzini and Florian M{\"a}rkl and Pedro Mesquita and Ruben Brabenec and Thadd{\"a}us Strzalkowski and Sophia Stock and Stefanos Michaelides and Johannes Hellmuth and Martin Thelen and Sarah Reinke and Wolfram Klapper and Gelebart, {Pascal Francois} and Leo Nicolai and Carsten Marr and Eduardo Beltr{\'a}n and Megens, {Remco T.A.} and Christoph Klein and Fanny Baran-Marszak and Andreas Rosenwald and {von Bergwelt-Baildon}, Michael and Br{\"o}ckelmann, {Paul J.} and Stefan Endres and Sebastian Kobold",

note = "Funding Information: This study was supported by the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich (grants 1138 [A.G.] and 1168 [S.S.]), the Bavarian Cancer Research Center (BZKF) (A.G. and TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, grant GO 3823/1-1 to A.G.; grants KO5055-2-1 and KO5055/3-1 to S.K.), the DKTK School of Oncology (A.G. and S.S.), the international doctoral program \u201Ci-Target: immunotargeting of cancer\u201D (funded by the Elite Network of Bavaria ; S.K. and S.E.), the Melanoma Research Alliance (grant 409510 to S.K.), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 program of the European Union; grant 955575 to S.K.), Else Kr\u00F6ner-Fresenius-Stiftung ( 2023_EKEA.19 to A.G., 2024 Excellence Stipend to P.J.B., and IOLIN to A.G. and S.K.), German Cancer Aid (Deutsche Krebshilfe, grant 70115514 to A.G. and AvantCAR.de to S.K.), the Wilhelm Sander-Stiftung (S.K.), Ernst Jung Stiftung (S.K.), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; S.E. and S.K.), the Go-Bio-Initiative (C.M. and S.K.), the m4-Award of the Bavarian Ministry for Economic Affairs (S.E. and S.K.), Bundesministerium f\u00FCr Bildung und Forschung (S.E. and S.K.), European Research Council (Starting grant 756017 , CoG 101124203 , and PoC grant 101100460 to S.K.), DFG ( KO5055-2-1 and 510821390 to S.K.), the SFB-TRR 338/1 2021-452881907 (S.K.), SFB 1123/Z1 (R.T.A.M.), Fritz Bender Foundation (S.K.), Deutsche Jos\u00E9 Carreras Leuk\u00E4mie-Stiftung (S.K.), Hector Foundation (S.K.), Monika-Kutzner Foundation for Cancer Research (S.K.), Bavarian Research Foundation (BAYCELLATOR to S.K.), the Bruno and Helene J\u00F6ster Foundation (360\u00B0 CAR to S.K.), and DFG (German Research Foundation) under Germany\u2019s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198; E.B.). M.T. is funded by the Volkswagen Foundation (project OntoTime). I.P. was supported by grants from the Bavarian Cancer Research Center (BZKF), the Stiftungen zu Gunsten der Medizinischen Fakult\u00E4t (Cluster 1), and the Novartis Foundation (InCa prize). C.M. has received funding from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement 866411) and support from the Hightech Agenda Bayern . R.G., G.V.H., J.J., V.I., T.A.J., T.L., A.\u00D6., and S.M. were supported by a grant from the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich. S.S. was supported by the Else Kr\u00F6ner-Fresenius Clinician Scientist Program Cancer Immunotherapy , the Munich Clinician Scientist Program, and the SFB-TRR 338 (startup funding). In vivo imaging device was funded by the DFG (German Research Foundation)\u2013INST 409/231-1, and the Leica SP8 3X confocal microscope was funded by LMUexcellent of LMU Munich and by the German Research Foundation (DFG) INST 409/150-1 FUGG (R.T.A.M.). Funding Information: Cytometry data were obtained in the Core Facility Flow Cytometry of the University Hospital, LMU Munich, using a BD LSRFortessa II or Beckman Coulter CytoFLEX. The authors acknowledge Life Science editors for their editing services. Figure illustrations were created with BioRender.com under a paid subscription. This study was supported by the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich (grants 1138 [A.G.] and 1168 [S.S.]), the Bavarian Cancer Research Center (BZKF) (A.G. and TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, grant GO 3823/1-1 to A.G.; grants KO5055-2-1 and KO5055/3-1 to S.K. Walter Benjamin-Program to D.S.), the DKTK School of Oncology (A.G. and S.S.), the international doctoral program \u201Ci-Target: immunotargeting of cancer\u201D (funded by the Elite Network of Bavaria; S.K. and S.E.), the Melanoma Research Alliance (grant 409510 to S.K.), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 program of the European Union; grant 955575 to S.K.) and Marie Sk\u0142odowska-Curie Doctoral Network Tracking and controlling therapeutic immune cells in cancer (TRAFIC) (grant agreement 101168810), Else Kr\u00F6ner-Fresenius-Stiftung (2023_EKEA.19 to A.G. 2024 Excellence Stipend to P.J.B. and IOLIN to A.G. S.S. and S.K.), German Cancer Aid (Deutsche Krebshilfe, grant 70115514 to A.G. AvantCAR.de to S.K. and Mildred-Scheel-Doktorandenprogramm to P.J.M.), the Wilhelm Sander-Stiftung (S.K.), Ernst Jung Stiftung (S.K.), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; to S.E. and S.K.), the Go-Bio-Initiative (C.M. and S.K.), the m4-Award of the Bavarian Ministry for Economic Affairs (S.E. and S.K.), Bundesministerium f\u00FCr Bildung und Forschung (S.E. and S.K. Eurostars to A.O.), European Research Council (Starting grant 756017, CoG 101124203, and PoC grant 101100460 to S.K.), DFG (grants KO5055-2-1 and 510821390 to S.K.), the SFB-TRR 338/1 2021-452881907 (S.K.), SFB 1123/Z1 (R.T.A.M.), Fritz Bender Foundation (S.K.), Deutsche Jos\u00E9 Carreras Leuk\u00E4mie-Stiftung (S.K.), Hector Foundation (S.K.), Monika-Kutzner Foundation for Cancer Research (S.K.), Bavarian Research Foundation (BAYCELLATOR to S.K.), the Bruno and Helene J\u00F6ster Foundation (360\u00B0 CAR to S.K.), and DFG (German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198; E.B.). M. Thomas is funded by the Volkswagen Foundation (project OntoTime). I.P. was supported by grants from the Bavarian Cancer Research Center (BZKF), the Stiftungen zu Gunsten der Medizinischen Fakult\u00E4t (Cluster 1), and the Novartis Foundation (InCa prize). C.K. and S.F.-W. have received funding from the Care for Rare Foundation, the Reinhard Frank-Stiftung (S.F.-W.), the Hector Foundation, the DFG (grant TRR332/B01 to C.K.) and the German Federal Ministry of Education and Research (BMBF) as part of the DZKJ (grant 01GL2406A to C.K.). C.M. has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement 866411) and support from the Hightech Agenda Bayern. R.G. G.V.H. J.J. V.I. T.A.J. T.L. A.\u00D6. and S.M. were supported by a grant from the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich. S.S. was supported by the Else Kr\u00F6ner-Fresenius Clinician Scientist Program Cancer Immunotherapy, the Munich Clinician Scientist Program, and the SFB-TRR 338 (startup funding). In vivo imaging device was funded by the DFG (German Research Foundation)\u2013INST 409/231-1, and the Leica SP8 3X confocal microscope was funded by LMUexcellent of LMU Munich and by the DFG INST 409/150-1 FUGG (R.T.A.M.). Contribution: A.G. R.G. G.V.H. S.N. A.\u00D6. R.K. J.G. I.P. H.S. V.I. D.B. L.d.F. M.M. T.A.J. E.C. C.A.T. M.P.T. P.M. M. Thelen, T.L. T.S. F.M. S.S. and S.M. performed or assisted with the in vitro and in vivo experiments; V.K. M. Thomas, D.S. R.B. C.M. and E.B. performed computational analyses; P.J.M. and J.J. performed multiplex immunohistochemistry; S.F.-W. and S.D.F. performed confocal imaging and provided bone marrow organoid; A.G. R.G. G.V.H. S.F. S.D.F. V.K. M. Thomas, D.S. M. Thelen, S.R. and R.B. analyzed the data; J.H. M. Thelen, S.R. W.K. P.F.G. L.N. E.B. R.T.A.M. C.K. F.B.-M. A.R. M.v.B.-B. and P.J.B. provided critical reagents or critical infrastructure; I.J. A.R. C.M. E.B. M.v.B.-B. S.E. and S.K. supported the project; A.G. R.G. G.V.H. S.N. and S.K. designed the experiments; A.G. C.M. E.B. M.v.B.-B. S.E. and S.K. supervised the project and acquired the funding; A.G. R.G. G.V.H. and S.K. conceptualized the data and prepared the figures; A.G. R.G. G.V.H. S.N. and S.K. wrote the manuscript; and all authors critically read and approved the final manuscript. Publisher Copyright: {\textcopyright} 2025 American Society of Hematology",

year = "2024",

month = dec,

doi = "10.1182/blood.2023022197",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

}

Gottschlich, A, Grünmeier, R, Hoffmann, GV, Nandi, S, Kavaka, V, Müller, PJ, Jobst, J, Oner, A, Kaiser, R, Gärtig, J, Piseddu, I, Frenz-Wiessner, S, Fairley, SD, Schulz, H, Igl, V, Janert, TA, Di Fina, L, Mulkers, M, Thomas, M, Briukhovetska, D, Simnica, D, Carlini, E, Tsiverioti, CA, Trefny, MP, Lorenzini, T, Märkl, F, Mesquita, P, Brabenec, R, Strzalkowski, T, Stock, S, Michaelides, S, Hellmuth, J, Thelen, M, Reinke, S, Klapper, W, Gelebart, PF, Nicolai, L, Marr, C, Beltrán, E, Megens, RTA, Klein, C, Baran-Marszak, F, Rosenwald, A, von Bergwelt-Baildon, M, Bröckelmann, PJ, Endres, S & Kobold, S 2024, 'Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma', Blood. https://doi.org/10.1182/blood.2023022197

TY - JOUR

T1 - Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

AU - Gottschlich, Adrian

AU - Grünmeier, Ruth

AU - Hoffmann, Gordon Victor

AU - Nandi, Sayantan

AU - Kavaka, Vladyslav

AU - Müller, Philipp Jie

AU - Jobst, Jakob

AU - Oner, Arman

AU - Kaiser, Rainer

AU - Gärtig, Jan

AU - Piseddu, Ignazio

AU - Frenz-Wiessner, Stephanie

AU - Fairley, Savannah D.

AU - Schulz, Heiko

AU - Igl, Veronika

AU - Janert, Thomas Alexander

AU - Di Fina, Lea

AU - Mulkers, Maité

AU - Thomas, Moritz

AU - Briukhovetska, Daria

AU - Simnica, Donjetë

AU - Carlini, Emanuele

AU - Tsiverioti, Christina Angeliki

AU - Trefny, Marcel P.

AU - Lorenzini, Theo

AU - Märkl, Florian

AU - Mesquita, Pedro

AU - Brabenec, Ruben

AU - Strzalkowski, Thaddäus

AU - Stock, Sophia

AU - Michaelides, Stefanos

AU - Hellmuth, Johannes

AU - Thelen, Martin

AU - Reinke, Sarah

AU - Klapper, Wolfram

AU - Gelebart, Pascal Francois

AU - Nicolai, Leo

AU - Marr, Carsten

AU - Beltrán, Eduardo

AU - Megens, Remco T.A.

AU - Klein, Christoph

AU - Baran-Marszak, Fanny

AU - Rosenwald, Andreas

AU - von Bergwelt-Baildon, Michael

AU - Bröckelmann, Paul J.

AU - Endres, Stefan

AU - Kobold, Sebastian

N1 - Funding Information: This study was supported by the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich (grants 1138 [A.G.] and 1168 [S.S.]), the Bavarian Cancer Research Center (BZKF) (A.G. and TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, grant GO 3823/1-1 to A.G.; grants KO5055-2-1 and KO5055/3-1 to S.K.), the DKTK School of Oncology (A.G. and S.S.), the international doctoral program \u201Ci-Target: immunotargeting of cancer\u201D (funded by the Elite Network of Bavaria ; S.K. and S.E.), the Melanoma Research Alliance (grant 409510 to S.K.), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 program of the European Union; grant 955575 to S.K.), Else Kr\u00F6ner-Fresenius-Stiftung ( 2023_EKEA.19 to A.G., 2024 Excellence Stipend to P.J.B., and IOLIN to A.G. and S.K.), German Cancer Aid (Deutsche Krebshilfe, grant 70115514 to A.G. and AvantCAR.de to S.K.), the Wilhelm Sander-Stiftung (S.K.), Ernst Jung Stiftung (S.K.), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; S.E. and S.K.), the Go-Bio-Initiative (C.M. and S.K.), the m4-Award of the Bavarian Ministry for Economic Affairs (S.E. and S.K.), Bundesministerium f\u00FCr Bildung und Forschung (S.E. and S.K.), European Research Council (Starting grant 756017 , CoG 101124203 , and PoC grant 101100460 to S.K.), DFG ( KO5055-2-1 and 510821390 to S.K.), the SFB-TRR 338/1 2021-452881907 (S.K.), SFB 1123/Z1 (R.T.A.M.), Fritz Bender Foundation (S.K.), Deutsche Jos\u00E9 Carreras Leuk\u00E4mie-Stiftung (S.K.), Hector Foundation (S.K.), Monika-Kutzner Foundation for Cancer Research (S.K.), Bavarian Research Foundation (BAYCELLATOR to S.K.), the Bruno and Helene J\u00F6ster Foundation (360\u00B0 CAR to S.K.), and DFG (German Research Foundation) under Germany\u2019s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198; E.B.). M.T. is funded by the Volkswagen Foundation (project OntoTime). I.P. was supported by grants from the Bavarian Cancer Research Center (BZKF), the Stiftungen zu Gunsten der Medizinischen Fakult\u00E4t (Cluster 1), and the Novartis Foundation (InCa prize). C.M. has received funding from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement 866411) and support from the Hightech Agenda Bayern . R.G., G.V.H., J.J., V.I., T.A.J., T.L., A.\u00D6., and S.M. were supported by a grant from the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich. S.S. was supported by the Else Kr\u00F6ner-Fresenius Clinician Scientist Program Cancer Immunotherapy , the Munich Clinician Scientist Program, and the SFB-TRR 338 (startup funding). In vivo imaging device was funded by the DFG (German Research Foundation)\u2013INST 409/231-1, and the Leica SP8 3X confocal microscope was funded by LMUexcellent of LMU Munich and by the German Research Foundation (DFG) INST 409/150-1 FUGG (R.T.A.M.). Funding Information: Cytometry data were obtained in the Core Facility Flow Cytometry of the University Hospital, LMU Munich, using a BD LSRFortessa II or Beckman Coulter CytoFLEX. The authors acknowledge Life Science editors for their editing services. Figure illustrations were created with BioRender.com under a paid subscription. This study was supported by the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich (grants 1138 [A.G.] and 1168 [S.S.]), the Bavarian Cancer Research Center (BZKF) (A.G. and TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, grant GO 3823/1-1 to A.G.; grants KO5055-2-1 and KO5055/3-1 to S.K. Walter Benjamin-Program to D.S.), the DKTK School of Oncology (A.G. and S.S.), the international doctoral program \u201Ci-Target: immunotargeting of cancer\u201D (funded by the Elite Network of Bavaria; S.K. and S.E.), the Melanoma Research Alliance (grant 409510 to S.K.), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 program of the European Union; grant 955575 to S.K.) and Marie Sk\u0142odowska-Curie Doctoral Network Tracking and controlling therapeutic immune cells in cancer (TRAFIC) (grant agreement 101168810), Else Kr\u00F6ner-Fresenius-Stiftung (2023_EKEA.19 to A.G. 2024 Excellence Stipend to P.J.B. and IOLIN to A.G. S.S. and S.K.), German Cancer Aid (Deutsche Krebshilfe, grant 70115514 to A.G. AvantCAR.de to S.K. and Mildred-Scheel-Doktorandenprogramm to P.J.M.), the Wilhelm Sander-Stiftung (S.K.), Ernst Jung Stiftung (S.K.), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; to S.E. and S.K.), the Go-Bio-Initiative (C.M. and S.K.), the m4-Award of the Bavarian Ministry for Economic Affairs (S.E. and S.K.), Bundesministerium f\u00FCr Bildung und Forschung (S.E. and S.K. Eurostars to A.O.), European Research Council (Starting grant 756017, CoG 101124203, and PoC grant 101100460 to S.K.), DFG (grants KO5055-2-1 and 510821390 to S.K.), the SFB-TRR 338/1 2021-452881907 (S.K.), SFB 1123/Z1 (R.T.A.M.), Fritz Bender Foundation (S.K.), Deutsche Jos\u00E9 Carreras Leuk\u00E4mie-Stiftung (S.K.), Hector Foundation (S.K.), Monika-Kutzner Foundation for Cancer Research (S.K.), Bavarian Research Foundation (BAYCELLATOR to S.K.), the Bruno and Helene J\u00F6ster Foundation (360\u00B0 CAR to S.K.), and DFG (German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy: ID 390857198; E.B.). M. Thomas is funded by the Volkswagen Foundation (project OntoTime). I.P. was supported by grants from the Bavarian Cancer Research Center (BZKF), the Stiftungen zu Gunsten der Medizinischen Fakult\u00E4t (Cluster 1), and the Novartis Foundation (InCa prize). C.K. and S.F.-W. have received funding from the Care for Rare Foundation, the Reinhard Frank-Stiftung (S.F.-W.), the Hector Foundation, the DFG (grant TRR332/B01 to C.K.) and the German Federal Ministry of Education and Research (BMBF) as part of the DZKJ (grant 01GL2406A to C.K.). C.M. has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement 866411) and support from the Hightech Agenda Bayern. R.G. G.V.H. J.J. V.I. T.A.J. T.L. A.\u00D6. and S.M. were supported by a grant from the F\u00F6rderprogramm f\u00FCr Forschung und Lehre of the Medical Faculty of the LMU Munich. S.S. was supported by the Else Kr\u00F6ner-Fresenius Clinician Scientist Program Cancer Immunotherapy, the Munich Clinician Scientist Program, and the SFB-TRR 338 (startup funding). In vivo imaging device was funded by the DFG (German Research Foundation)\u2013INST 409/231-1, and the Leica SP8 3X confocal microscope was funded by LMUexcellent of LMU Munich and by the DFG INST 409/150-1 FUGG (R.T.A.M.). Contribution: A.G. R.G. G.V.H. S.N. A.\u00D6. R.K. J.G. I.P. H.S. V.I. D.B. L.d.F. M.M. T.A.J. E.C. C.A.T. M.P.T. P.M. M. Thelen, T.L. T.S. F.M. S.S. and S.M. performed or assisted with the in vitro and in vivo experiments; V.K. M. Thomas, D.S. R.B. C.M. and E.B. performed computational analyses; P.J.M. and J.J. performed multiplex immunohistochemistry; S.F.-W. and S.D.F. performed confocal imaging and provided bone marrow organoid; A.G. R.G. G.V.H. S.F. S.D.F. V.K. M. Thomas, D.S. M. Thelen, S.R. and R.B. analyzed the data; J.H. M. Thelen, S.R. W.K. P.F.G. L.N. E.B. R.T.A.M. C.K. F.B.-M. A.R. M.v.B.-B. and P.J.B. provided critical reagents or critical infrastructure; I.J. A.R. C.M. E.B. M.v.B.-B. S.E. and S.K. supported the project; A.G. R.G. G.V.H. S.N. and S.K. designed the experiments; A.G. C.M. E.B. M.v.B.-B. S.E. and S.K. supervised the project and acquired the funding; A.G. R.G. G.V.H. and S.K. conceptualized the data and prepared the figures; A.G. R.G. G.V.H. S.N. and S.K. wrote the manuscript; and all authors critically read and approved the final manuscript. Publisher Copyright: © 2025 American Society of Hematology

PY - 2024/12

Y1 - 2024/12

N2 - The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell–based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86–CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

AB - The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell–based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86–CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

U2 - 10.1182/blood.2023022197

DO - 10.1182/blood.2023022197

M3 - Article

SN - 0006-4971

JO - Blood

JF - Blood

ER -

Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma

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