Top

Published in:

01-06-2020 | Lymphoma | Original Article

Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas

Authors: Melissa Alame, Marion Pirel, Valérie Costes-Martineau, Luc Bauchet, Michel Fabbro, Alicia Tourneret, Laura De Oliveira, Luc Durand, Pascal Roger, Samia Gonzalez, Valère Cacheux, Valérie Rigau, Vanessa Szablewski

Published in: Virchows Archiv | Issue 6/2020

Abstract

Primary central nervous system diffuse large B cell lymphoma (PCNS-DLBCL) is a rare and aggressive entity of diffuse large B cell lymphoma (DLBCL). Elements of the tumour microenvironment (TME) including tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) have been associated with survival in DLBCL but their composition and prognostic impact in PCNS-DLBCL are unknown. Programmed cell death-1 (PD1)/programmed death-ligand 1 (PD-L1) immune checkpoint may represent a therapeutic option. Here, we aimed to characterise PD1/PDL1 immune checkpoints and the composition of the TME in PCNS-DLBCL. We collected tumour tissue and clinical data from 57 PCNS-DLBCL and used immunohistochemistry to examine TAMs (CD68, CD163), TILs (CD3, CD4, CD8, PD1) and tumour B cells (PAX5/PDL1 double stains, PDL1). The PDL1 gene was evaluated by fluorescence in situ hybridization (FISH). PAX5/PDL1 identified PDL1 expression by tumour B cells in 10/57 cases (17.5%). PDL1 gene translocation was a recurrent cytogenetic alteration in PNCS-DLBCL (8/47.17%) and was correlated with PDL1 positive expression in tumour B cells. The TME consisted predominantly of CD163 (+) M2 TAMs and CD8 (+) TILs. Most TAMs expressed PDL1 and most TILs expressed PD1. The density of TAMs and TILs did not associate with outcome. We showed that expression of PD1 on TILs and PDL1 on TAMs, but not the expression of PDL1 on tumour B cells was correlated with better prognosis. These findings support a significant role of TME composition and PD1/PDL1 crosstalk in PCNS-DLBCL pathogenesis and bring new insights to the targeted therapy of this aggressive lymphoma.

Available only for authorised users

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, Gascoyne RD (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885. https://doi.org/10.1056/NEJMoa0905680 CrossRefPubMedPubMedCentral

Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI, Bartlett NL, Advani RH, Buckstein R, Rimsza LM, Connors JM, Steidl C, Gordon LI, Horning SJ, Gascoyne RD (2012) Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 intergroup trial. Blood 120:3280–3287. https://doi.org/10.1182/blood-2012-04-421057 CrossRefPubMedPubMedCentral

Jakovic LR, Mihaljevic BS, Perunicic Jovanovic MD, Bogdanovic AD, Andjelic BM, Bumbasirevic VZ (2011) The prognostic relevance of tumor associated macrophages in advanced stage classical Hodgkin lymphoma. Leuk Lymphoma 52:1913–1919. https://doi.org/10.3109/10428194.2011.580026 CrossRefPubMed

Leivonen S-K, Pollari M, Brück O, Pellinen T, Autio M, Karjalainen-Lindsberg M-L et al (2018) T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma. Haematologica. https://doi.org/10.3324/haematol.2018.200105

Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M (2013) CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am J Hematol 88:273–276. https://doi.org/10.1002/ajh.23398 CrossRefPubMed

Xu Y, Kroft SH, McKenna RW, Aquino DB (2001) Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study. Br J Haematol 112:945–949CrossRefPubMed

Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE (2001) Cd4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol Off J Am Soc Clin Oncol 19:720–726. https://doi.org/10.1200/JCO.2001.19.3.720 CrossRef

Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, Sugita Y, Yufu Y, Choi I, Abe Y, Uike N, Nagafuji K, Okamura T, Akashi K, Takayanagi R, Shiratsuchi M, Ohshima K (2015) Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 126:2193–2201. https://doi.org/10.1182/blood-2015-02-629600 CrossRefPubMedPubMedCentral

Wang Y, Wu L, Tian C, Zhang Y (2017) PD-1-PD-L1 immune-checkpoint blockade in malignant lymphomas. Ann Hematol 97:229–237. https://doi.org/10.1007/s00277-017-3176-6 CrossRefPubMed

10.

Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res Off J Am Assoc Cancer Res 20:5064–5074. https://doi.org/10.1158/1078-0432.CCR-13-3271 CrossRef

11.

Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA et al (2019) Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: a single-arm, phase II study. J Clin Oncol Off J Am Soc Clin Oncol:JCO1800766. https://doi.org/10.1200/JCO.18.00766

12.

von Keudell G, Younes A (2019) Novel therapeutic agents for relapsed classical Hodgkin lymphoma. Br J Haematol 184:105–112. https://doi.org/10.1111/bjh.15695 CrossRef

13.

Oliva S, Troia R, D’Agostino M, Boccadoro M, Gay F (2018) Promises and pitfalls in the use of PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol 9:2749. https://doi.org/10.3389/fimmu.2018.02749 CrossRefPubMedPubMedCentral

14.

Dong Z-Y, Wu S-P, Liao R-Q, Huang S-M, Wu Y-L (2016) Potential biomarker for checkpoint blockade immunotherapy and treatment strategy. Tumour Biol J Int Soc Oncodevelopmental Biol Med 37:4251–4261. https://doi.org/10.1007/s13277-016-4812-9 CrossRef

15.

Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD, Chan WC, Zhao T, Haioun C, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Campo E, Montserrat E, Lopez-Guillermo A, Ott G, Muller-Hermelink HK, Connors JM, Braziel R, Grogan TM, Fisher RI, Miller TP, LeBlanc M, Chiorazzi M, Zhao H, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Staudt LM (2003) Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198:851–862. https://doi.org/10.1084/jem.20031074 CrossRefPubMedPubMedCentral

16.

Joos S, Otaño-Joos MI, Ziegler S, Brüderlein S, du Manoir S, Bentz M et al (1996) Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87:1571–1578CrossRefPubMed

17.

Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E et al (2010) Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268–3277. https://doi.org/10.1182/blood-2010-05-282780 CrossRefPubMedPubMedCentral

18.

Van Roosbroeck K, Ferreiro JF, Tousseyn T, van der Krogt J-A, Michaux L, Pienkowska-Grela B et al (2016) Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies. Genes Chromosomes Cancer 55:428–441. https://doi.org/10.1002/gcc.22345 CrossRefPubMed

19.

Chapuy B, Roemer MGM, Stewart C, Tan Y, Abo RP, Zhang L et al (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869–881. https://doi.org/10.1182/blood-2015-10-673236 CrossRefPubMedPubMedCentral

20.

Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S et al (2012) Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol Off J Am Soc Clin Oncol. https://doi.org/10.1200/JCO.2011.41.0985

21.

Chatzitolios A, Venizelos I, Tripsiannis G, Anastassopoulos G, Papadopoulos N (2010) Prognostic significance of CD95, P53, and BCL2 expression in extranodal non-Hodgkin’s lymphoma. Ann Hematol 89:889–896. https://doi.org/10.1007/s00277-010-0945-x CrossRefPubMed

22.

Shukuya T, Carbone DP (2016) Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. https://doi.org/10.1016/j.jtho.2016.02.015

23.

Krishnan C, Warnke RA, Arber DA, Natkunam Y (2010) PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol 34:178–189. https://doi.org/10.1097/PAS.0b013e3181cc7e79 CrossRefPubMed

24.

Kwon D, Kim S, Kim P-J, Go H, Nam SJ, Paik JH, Kim YA, Kim TM, Heo DS, Kim CW, Jeon YK (2016) Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas. Histopathology 68:1079–1089. https://doi.org/10.1111/his.12882 CrossRefPubMed

25.

Carey CD, Gusenleitner D, Lipschitz M, Roemer MGM, Stack EC, Gjini E, Hu X, Redd R, Freeman GJ, Neuberg D, Hodi FS, Liu XS, Shipp MA, Rodig SJ (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420–2430. https://doi.org/10.1182/blood-2017-03-770719 CrossRefPubMedPubMedCentral

26.

Laurent C, Charmpi K, Gravelle P, Tosolini M, Franchet C, Ysebaert L, Brousset P, Bidaut A, Ycart B, Fournié JJ (2015) Several immune escape patterns in non-Hodgkin’s lymphomas. Oncoimmunology 4:e1026530. https://doi.org/10.1080/2162402X.2015.1026530 CrossRefPubMedPubMedCentral

27.

Menter T, Bodmer-Haecki A, Dirnhofer S, Tzankov A (2016) Evaluation of the diagnostic and prognostic value of PDL1-expression in Hodgkin and B-cell lymphomas. Hum Pathol. https://doi.org/10.1016/j.humpath.2016.03.005

28.

Qiu L, Zheng H, Zhao X (2019) The prognostic and clinicopathological significance of PD-L1 expression in patients with diffuse large B-cell lymphoma: a meta-analysis. BMC Cancer 19:273. https://doi.org/10.1186/s12885-019-5466-y CrossRefPubMedPubMedCentral

29.

30.

Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MGM, Xu ML, Yu H, Fletcher CD, Freeman GJ, Shipp MA, Rodig SJ (2013) PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res Off J Am Assoc Cancer Res 19:3462–3473. https://doi.org/10.1158/1078-0432.CCR-13-0855 CrossRef

31.

Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim K-H, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470:115–119. https://doi.org/10.1038/nature09671 CrossRefPubMed

32.

Montesinos-Rongen M, Van Roost D, Schaller C, Wiestler OD, Deckert M (2004) Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 103:1869–1875. https://doi.org/10.1182/blood-2003-05-1465 CrossRefPubMed

33.

Twa DDW, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A, Tan KL, Slack GW, Gunawardana J, Lim RS, McPherson A, Kridel R, Telenius A, Scott DW, Savage KJ, Shah SP, Gascoyne RD, Steidl C (2014) Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123:2062–2065. https://doi.org/10.1182/blood-2013-10-535443 CrossRefPubMed

34.

Zhou XA, Louissaint A, Wenzel A, Yang J, Martinez-Escala ME, Moy AP et al (2018) Genomic analyses identify recurrent alterations in immune evasion genes in diffuse large B-cell lymphoma, leg type. J Invest Dermatol 138:2365–2376. https://doi.org/10.1016/j.jid.2018.04.038 CrossRefPubMedPubMedCentral

35.

Georgiou K, Chen L, Berglund M, Ren W, de Miranda NFCC, Lisboa S, Fangazio M, Zhu S, Hou Y, Wu K, Fang W, Wang X, Meng B, Zhang L, Zeng Y, Bhagat G, Nordenskjöld M, Sundström C, Enblad G, Dalla-Favera R, Zhang H, Teixeira MR, Pasqualucci L, Peng R, Pan-Hammarström Q (2016) Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood 127:3026–3034. https://doi.org/10.1182/blood-2015-12-686550 CrossRefPubMed

36.

Pardoll DM, Topalian SL (1998) The role of CD4+ T cell responses in antitumor immunity. Curr Opin Immunol 10:588–594CrossRefPubMed

37.

Steele KE, Tan TH, Korn R, Dacosta K, Brown C, Kuziora M, Zimmermann J, Laffin B, Widmaier M, Rognoni L, Cardenes R, Schneider K, Boutrin A, Martin P, Zha J, Wiestler T (2018) Measuring multiple parameters of CD8+ tumor-infiltrating lymphocytes in human cancers by image analysis. J Immunother Cancer 6:20–14. https://doi.org/10.1186/s40425-018-0326-x CrossRefPubMedPubMedCentral

38.

Alvaro-Naranjo T, Lejeune M, Salvadó-Usach MT, Bosch-Príncep R, Reverter-Branchat G, Jaén-Martínez J, Pons-Ferré LE (2005) Tumor-infiltrating cells as a prognostic factor in Hodgkin’s lymphoma: a quantitative tissue microarray study in a large retrospective cohort of 267 patients. Leuk Lymphoma 46:1581–1591. https://doi.org/10.1080/10428190500220654 CrossRefPubMed

39.

Alonso-Álvarez S, Vidriales MB, Caballero MD, Blanco O, Puig N, Martin A, Peñarrubia MJ, Zato E, Galende J, Bárez A, Alcoceba M, Orfão A, González M, García-Sanz R (2017) The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy. Leuk Lymphoma 58:1144–1152. https://doi.org/10.1080/10428194.2016.1239263 CrossRefPubMed

40.

McClanahan F, Sharp TG, Gribben JG (2016) Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas? Haematologica 101:1144–1158. https://doi.org/10.3324/haematol.2016.145904 CrossRefPubMedPubMedCentral

41.

Pollari M, Brück O, Pellinen T, Vähämurto P, Karjalainen-Lindsberg M-L, Mannisto S, Kallioniemi O, Kellokumpu-Lehtinen PL, Mustjoki S, Leivonen SK, Leppä S (2018) PD-L1+ tumor-associated macrophages and PD-1+ tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma. Haematologica 103:1908–1914. https://doi.org/10.3324/haematol.2018.197194 CrossRefPubMedPubMedCentral

42.

Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604. https://doi.org/10.1016/j.immuni.2010.05.007 CrossRefPubMed

43.

Biswas SK, Chittezhath M, Shalova IN, Lim J-Y (2012) Macrophage polarization and plasticity in health and disease. Immunol Res 53:11–24. https://doi.org/10.1007/s12026-012-8291-9 CrossRefPubMed

44.

Adema GJ, Hartgers F, Verstraten R, de Vries E, Marland G, Menon S, Foster J, Xu Y, Nooyen P, McClanahan T, Bacon KB, Figdor CG (1997) A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Nature 387:713–717. https://doi.org/10.1038/42716 CrossRefPubMed

45.

Hu H, Nie Y, Huang H, Guo M, Chen J, Wu W et al (2019) Breast phyllodes tumors recruit and repolarize tumor-associated macrophages via secreting CCL5 to promote malignant progression which can be inhibited by CCR5 inhibition therapy. Clin Cancer Res Off J Am Assoc Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-3421

46.

Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B et al (2018) Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle Georget Tex 17:428–438. https://doi.org/10.1080/15384101.2018.1444305 CrossRef

47.

Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254–265. https://doi.org/10.1002/path.1027 CrossRefPubMed

48.

Nam SJ, Go H, Paik JH, Kim TM, Heo DS, Kim CW, Jeon YK (2014) An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Leuk Lymphoma 55:2466–2476. https://doi.org/10.3109/10428194.2013.879713 CrossRefPubMed

49.

Menguy S, Prochazkova-Carlotti M, Beylot-Barry M, Saltel F, Vergier B, Merlio J-P et al (2017) PD-L1 and PD-L2 are differentially expressed by macrophages or tumor cells in primary cutaneous diffuse large B-cell lymphoma. Leg Type Am J Surg Pathol. https://doi.org/10.1097/PAS.0000000000000983

50.

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-2017-01-764209 CrossRefPubMedPubMedCentral

Title: Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas
Authors: Melissa Alame
Marion Pirel
Valérie Costes-Martineau
Luc Bauchet
Michel Fabbro
Alicia Tourneret
Laura De Oliveira
Luc Durand
Pascal Roger
Samia Gonzalez
Valère Cacheux
Valérie Rigau
Vanessa Szablewski
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keywords: Lymphoma
Fluorescence in Situ Hybridization
Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Published in: Virchows Archiv / Issue 6/2020
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-019-02695-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2020

The autopsy debate during the COVID-19 emergency: the Italian experience

Histotype-specific analysis of acid ceramidase expression in ovarian cancer

Matrix-assisted laser desorption/ionization mass spectrometry imaging to uncover protein alterations associated with the progression of IgA nephropathy

ALK-rearranged renal cell carcinoma with a novel PLEKHA7-ALK translocation and metanephric adenoma-like morphology

Higher density of stromal M2 macrophages in breast ductal carcinoma in situ predicts recurrence

Histopathological and molecular study for synchronous lung adenocarcinoma staging