Top

Published in:

01-09-2020 | Lymphoma | Original Article

In-depth characterization of the tumor microenvironment in central nervous system lymphoma reveals implications for immune-checkpoint therapy

Authors: Lukas Marcelis, Asier Antoranz, Anne-Marie Delsupehe, Pauline Biesemans, Julio Finalet Ferreiro, Koen Debackere, Peter Vandenberghe, Gregor Verhoef, Olivier Gheysens, Giorgio Cattoretti, Francesca Maria Bosisio, Xavier Sagaert, Daan Dierickx, Thomas Tousseyn

Published in: Cancer Immunology, Immunotherapy | Issue 9/2020

Abstract

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma with an aggressive clinical course. To investigate the potential of immune-checkpoint therapy, we retrospectively studied the tumor microenvironment (TME) using high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 “other” CNSL lymphomas with the presence of the Epstein–Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition and the functional spectrum of cytotoxic T cells were similar. But cytotoxic T cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T cells and geographic-type necrosis each predicted inferior outcome in PCNSL. Both M1-like (CD68 + CD163^low) and M2-like (CD68 + CD163^high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated with a better survival. PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0.4% of all CD8+ T cells. TIM-3, a marker for T cell exhaustion, was significantly more expressed in CD8^posPD-1^pos T cells compared to CD8^posPD-1^neg T cells, and a similar increased expression was observed in M2-like pro-tumoral phagocytes. In conclusion, the clinical impact of TME composition supports the use of immune-checkpoint therapies in PCNSL. Based on observed differences in immune-checkpoint expression, combinations that boost cytotoxic T cell activation (by blocking TIM-3 or TGFBR1) prior to the administration of PD-L1 inhibition could be of interest.

Available only for authorised users

Kluin PM, Deckert M, Ferry JA (2017) Primary diffuse large B-cell lymphoma of the CNS. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, revised 4th. IARC, Lyon, pp 300–302

Montesinos-Rongen M, Siebert R, Deckert M (2009) Primary lymphoma of the central nervous system: just DLBCL or not? Blood 113:7–10. https://doi.org/10.1182/blood-2008-04-149005CrossRefPubMed

Chang C, Lin C-H, Cheng A-L, Medeiros LJ, Chang K-C (2015) Primary central nervous system diffuse large B-cell lymphoma has poorer immune cell infiltration and prognosis than its peripheral counterpart. Histopathology 67:625–635. https://doi.org/10.1111/his.12706CrossRefPubMed

Marcelis L, Charlien B, De Zutter A, Biesemans P, Vandenberghe P, Verhoef G, Gheysens O, Sagaert X, Dierickx D, Tousseyn T (2018) Other immunomodulatory/suppressive lymphoproliferative diseases: a single-center series of 72 biopsy confirmed cases. Mod Pathol 31:1457–1469CrossRefPubMed

Scott DW, Gascoyne RD (2014) The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 14:517–534. https://doi.org/10.1038/nrc3774CrossRefPubMed

Fowler NH, Cheah CY, Gascoyne RD, Gribben J, Neelapu SS, Ghia P, Bollard C, Ansell S, Curran M, Wilson WH, O’Brien S, Grant C, Little R, Zenz T, Nastoupil LJ, Dunleavy K et al (2016) Role of the tumor microenvironment in mature B-cell lymphoid malignancies. Haematologica 101:531–540. https://doi.org/10.3324/haematol.2015.139493CrossRefPubMedPubMedCentral

Ponzoni M, Berger F, Clement C, Tinguely M, Jouvet A, Ferreri AJM, DellOro S, Terreni MR, Doglioni C, Weis J, Cerati M, Milani M, Iuzzolino P, Motta T, Carbone A, Pedrinis E, Sanchez J, Blay J-Y, Reni M, Conconi A, Bertoni F, Zucca E, Cavalli F, Borisch B, International Extranodal Lymphoma Study Group (2007) Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas. Br J Haematol 138:316–323. https://doi.org/10.1111/j.1365-2141.2007.06661.xCrossRefPubMed

Kumari N, Krishnani N, Rawat A, Agarwal V, Lal P (2009) Primary central nervous system lymphoma: prognostication as per international extranodal lymphoma study group score and reactive CD3 collar. J Postgrad Med 55:247–251. https://doi.org/10.4103/0022-3859.58926CrossRefPubMed

Komohara Y, Horlad H, Ohnishi K, Ohta K, Makino K, Hondo H, Yamanaka R, Kajiwara K, Saito T, Kuratsu J, Takeya M (2011) M2 macrophage/microglial cells induce activation of Stat3 in primary central nervous system lymphoma. J Clin Exp Hematop 51:93–99CrossRefPubMed

10.

He M, Zuo C, Wang J, Liu J, Jiao B, Zheng J, Cai Z (2013) Prognostic significance of the aggregative perivascular growth pattern of tumor cells in primary central nervous system diffuse large B-cell lymphoma. Neuro Oncol 15:727–734. https://doi.org/10.1093/neuonc/not012CrossRefPubMedPubMedCentral

11.

Four M, Cacheux V, Tempier A, Platero D, Fabbro M, Marin G, Leventoux N, Rigau V, Costes-Martineau V, Szablewski V (2017) PD1 and PDL1 expression in primary central nervous system diffuse large B-cell lymphoma are frequent and expression of PD1 predicts poor survival. Hematol Oncol 35:487–496. https://doi.org/10.1002/hon.2375CrossRefPubMed

12.

Sasayama T, Tanaka K, Mizowaki T, Nagashima H, Nakamizo S, Tanaka H, Nishihara M, Mizukawa K, Hirose T, Itoh T, Kohmura E (2016) Tumor-associated macrophages associate with cerebrospinal fluid interleukin-10 and survival in primary central nervous system lymphoma (PCNSL). Brain Pathol 26:479–487. https://doi.org/10.1111/bpa.12318CrossRefPubMed

13.

Cho H, Kim S-JSH, Kim S-JSH, Chang JH, Yang WI, Suh C-O, Cheong J-W, Kim YR, Lee JY, Jang JE, Kim YR, Min YH, Kim JS (2017) The prognostic role of CD68 and FoxP3 expression in patients with primary central nervous system lymphoma. Ann Hematol 96:1163–1173. https://doi.org/10.1007/s00277-017-3014-xCrossRefPubMed

14.

Cho H, Kim SH, Kim S-J, Chang JH, Yang W-I, Suh C-O, Kim YR, Jang JE, Cheong J-W, Min YH, Kim JS (2017) Programmed cell death 1 expression is associated with inferior survival in patients with primary central nervous system lymphoma. Oncotarget 8:87317–87328. https://doi.org/10.18632/oncotarget.20264CrossRefPubMedPubMedCentral

15.

Chapuy B, Roemer MGM, Stewart C, Tan Y, Abo RP, Zhang L, Dunford AJ, Meredith DM, Thorner AR, Jordanova ES, Liu G, Feuerhake F, Ducar MD, Illerhaus G, Gusenleitner D, Linden EA, Sun HH, Homer H, Aono M, Pinkus GS, Ligon AH, Ligon KL, Ferry JA, Freeman GJ, van Hummelen P, Golub TR, Getz G, Rodig SJ, de Jong D, Monti S, Shipp MA (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869–881. https://doi.org/10.1182/blood-2015-10-673236CrossRefPubMedPubMedCentral

16.

Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, Armand P, Rodig SJ, Shipp MA (2017) PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129:3071–3073. https://doi.org/10.1182/blood-2017-01-764209CrossRefPubMedPubMedCentral

17.

Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150. https://doi.org/10.1038/s41568-019-0116-xCrossRefPubMedPubMedCentral

18.

Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541:321–330. https://doi.org/10.1038/nature21349CrossRefPubMed

19.

Bosisio FM, Antoranz A, van Herck Y, Bolognesi MM, Marcelis L, Chinello C, Wouters J, Magni F, Alexopoulos L, Stas M, Boecxstaens V, Bechter O, Cattoretti G, van den Oord J (2020) Functional heterogeneity of lymphocytic patterns in primary melanoma dissected through single-cell multiplexing. Elife 9:1–28. https://doi.org/10.7554/elife.53008CrossRef

20.

Miyasato Y, Takashima Y, Takeya H, Yano H, Hayano A, Nakagawa T, Makino K, Takeya M, Yamanaka R, Komohara Y (2018) The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma. J Clin Exp Hematop 58:95–101. https://doi.org/10.3960/jslrt.18001CrossRefPubMedPubMedCentral

21.

Illerhaus G, Schorb E, Kasenda B (2018) Novel agents for primary central nervous system lymphoma: evidence and perspectives. Blood 132:681–688. https://doi.org/10.1182/blood-2018-01-791558CrossRefPubMed

22.

Bolognesi MM, Manzoni M, Scalia CR, Zannella S, Bosisio FM, Faretta M, Cattoretti G (2017) Multiplex staining by sequential immunostaining and antibody removal on routine tissue sections. J Histochem Cytochem 65:431–444. https://doi.org/10.1369/0022155417719419CrossRefPubMedPubMedCentral

23.

Cattoretti G, Cattoretti G, Bosisio FM, Marcelis L, Bolognesi MM (2018) Multiple iteractive labeling by antibody neodeposition (MILAN). Protoc Exch. https://doi.org/10.1038/protex.2018.106CrossRef

24.

Morscio J, Dierickx D, Ferreiro JF, Herreman A, Van Loo P, Bittoun E, Verhoef G, Matthys P, Cools J, Wlodarska I, De Wolf-Peeters C, Sagaert X, Tousseyn T (2013) Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders. Am J Transplant 13:1305–1316. https://doi.org/10.1111/ajt.12196CrossRefPubMed

25.

Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG, James JA, Salto-Tellez M, Hamilton PW (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16878. https://doi.org/10.1038/s41598-017-17204-5CrossRefPubMedPubMedCentral

26.

Blaker YN, Spetalen S, Brodtkorb M, Lingjærde OC, Beiske K, Østenstad B, Sander B, Wahlin BE, Melen CM, Myklebust JH, Holte H, Delabie J, Smeland EB (2016) The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era. Br J Haematol 175:102–114. https://doi.org/10.1111/bjh.14201CrossRefPubMed

27.

Gomez-Gelvez JC, Salama ME, Perkins SL, Leavitt M, Inamdar KV (2016) Prognostic impact of tumor microenvironment in diffuse large B-cell lymphoma uniformly treated with R-CHOP chemotherapy. Am J Clin Pathol 145:514–523. https://doi.org/10.1093/AJCP/AQW034CrossRefPubMed

28.

Camilleri-Broët S, Criniè E, Broët P, Delwail V, Mokhtari K, Moreau A, Kujas M, Raphaël M, Iraqi W, Sautès-Fridman C, Colombat P, Hoang-Xuan K, Martin A (2006) Auniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 107:190–196. https://doi.org/10.1182/blood-2005-03-1024CrossRefPubMed

29.

Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, Khodadoust MS, Esfahani MS, Luca BA, Steiner D, Diehn M, Alizadeh AA (2019) Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 37:773–782. https://doi.org/10.1038/s41587-019-0114-2CrossRefPubMedPubMedCentral

30.

Marcelis L, Tousseyn T (2019) The tumor microenvironment in post-transplant lymphoproliferative disorders. Cancer Microenviron 12:3–16. https://doi.org/10.1007/s12307-018-00219-5CrossRefPubMedPubMedCentral

31.

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341. https://doi.org/10.1038/nature14432CrossRefPubMedPubMedCentral

32.

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999. https://doi.org/10.1084/jem.20142290CrossRefPubMedPubMedCentral

33.

Grywalska E, Pasiarski M, Góźdź S, Roliński J (2018) Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer. Onco Targets Ther 11:6505–6524. https://doi.org/10.2147/OTT.S150817CrossRefPubMedPubMedCentral

34.

Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, Wu K (2018) Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 17:129. https://doi.org/10.1186/s12943-018-0864-3CrossRefPubMedPubMedCentral

35.

Gravelle P, Burroni B, Péricart S, Rossi C, Bezombes C, Tosolini M, Damotte D, Brousset P, Fournié J-J, Laurent C (2017) Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of immunohistochemical studies. Oncotarget 8:44960–44975. https://doi.org/10.18632/oncotarget.16680CrossRefPubMedPubMedCentral

36.

Nayyar N, White MD, Gill CM, Lastrapes M, Bertalan M, Kaplan A, D’Andrea MR, Bihun I, Kaneb A, Dietrich J, Ferry JA, Martinez-Lage M, Giobbie-Hurder A, Borger DR, Rodriguez FJ, Frosch MP, Batchelor E, Hoang K, Kuter B, Fortin S, Holdhoff M, Cahill DP, Carter S, Brastianos PK, Batchelor TT (2019) MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas. Blood Adv 3:375–383. https://doi.org/10.1182/bloodadvances.2018027672CrossRefPubMedPubMedCentral

37.

Ahn E, Araki K, Hashimoto M, Li W, Riley JL, Cheung J, Sharpe AH, Freeman GJ, Irving BA, Ahmed R (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci USA 115:4749–4754. https://doi.org/10.1073/pnas.1718217115CrossRefPubMedPubMedCentral

38.

Mita Y, Kimura MY, Hayashizaki K, Koyama-Nasu R, Ito T, Motohashi S, Okamoto Y, Nakayama T (2018) Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells. Int Immunol 30:559–567. https://doi.org/10.1093/intimm/dxy050CrossRefPubMed

39.

Kamper P, Bendix K, Hamilton-Dutoit S, Honoré B, Nyengaard JR et al (2011) Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein–Barr virus status in classical Hodgkin’s lymphoma. Haematologica 96:269–276. https://doi.org/10.3324/haematol.2010.031542CrossRefPubMed

40.

Quaranta V, Schmid MC (2019) Macrophage-mediated subversion of anti-tumour immunity. Cells 8:747. https://doi.org/10.3390/cells8070747CrossRefPubMedCentral

41.

He Y, Cao J, Zhao C, Li X, Zhou C, Hirsch FR (2018) TIM-3, a promising target for cancer immunotherapy. Onco Targets Ther 11:7005–7009. https://doi.org/10.2147/OTT.S170385CrossRefPubMedPubMedCentral

42.

Stelling A, Hashwah H, Bertram K, Manz MG, Tzankov A, Müller A (2018) The tumor suppressive TGF-b/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. Blood 131:2235–2246. https://doi.org/10.1182/blood-2017-10-810630CrossRefPubMed

43.

Batlle E, Massagué J (2019) Transforming growth factor-β signaling in immunity and cancer. Immunity 50:924–940. https://doi.org/10.1016/j.immuni.2019.03.024CrossRefPubMedPubMedCentral

44.

Zöller T, Schneider A, Kleimeyer C, Masuda T, Potru PS, Pfeifer D, Blank T, Prinz M, Spittau B (2018) Silencing of TGFβ signalling in microglia results in impaired homeostasis. Nat Commun 9:1–13. https://doi.org/10.1038/s41467-018-06224-yCrossRef

45.

Dierickx D, Tousseyn T, Verhoef G, Moyer A (2010) Primary central nervous system post-transplatation lymphoproliferative disorder. Cancer 116:3521. https://doi.org/10.1002/cncr.25340CrossRefPubMed

Title: In-depth characterization of the tumor microenvironment in central nervous system lymphoma reveals implications for immune-checkpoint therapy
Authors: Lukas Marcelis
Asier Antoranz
Anne-Marie Delsupehe
Pauline Biesemans
Julio Finalet Ferreiro
Koen Debackere
Peter Vandenberghe
Gregor Verhoef
Olivier Gheysens
Giorgio Cattoretti
Francesca Maria Bosisio
Xavier Sagaert
Daan Dierickx
Thomas Tousseyn
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keywords: Lymphoma
Epstein-Barr Virus
Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Published in: Cancer Immunology, Immunotherapy / Issue 9/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02575-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 9/2020

Cysteine cathepsins L and X differentially modulate interactions between myeloid-derived suppressor cells and tumor cells

IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18

Peri-tumor administration of controlled release anti-CTLA-4 synergizes with systemic anti-PD-1 to induce systemic antitumor immunity while sparing autoimmune toxicity

Impact of corticosteroids on allograft protection in renal transplant patients receiving anti-PD-1 immunotherapy

Rapid noninvasive detection of bladder cancer using survivin antibody-conjugated gold nanoparticles (GNPs) based on localized surface plasmon resonance (LSPR)

A gene expression-based immune signature for lung adenocarcinoma prognosis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer