Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lymphoma

A novel lymphoma-associated macrophage interaction signature (LAMIS) provides robust risk prognostication in diffuse large B-cell lymphoma clinical trial cohorts of the DSHNHL

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2–2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2–2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3–2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. International Agency for Research on Cancer: Lyon; 2017.

  2. 2.

    Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.

    Article  CAS  Google Scholar 

  3. 3.

    Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937–47.

    Article  PubMed  Google Scholar 

  4. 4.

    Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171:481–94. e15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. New Engl J Med. 2018;378:1396–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Horn H, Ziepert M, Becher C, Barth TFE, Bernd H-W, Feller AC, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121:2253–63.

    Article  CAS  Google Scholar 

  8. 8.

    Klapper W, Stoecklein H, Zeynalova S, Ott G, Kosari F, Rosenwald A, et al. Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Leukemia. 2008;22:2226–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Alizadeh AA, Gentles AJ, Alencar AJ, Liu CL, Kohrt HE, Houot R, et al. Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. Blood. 2011;118:1350–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F, Gonzalez-Barca E, Mercadal S, Mate JL, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117:4836–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M. CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am J Hematol. 2013;88:273–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359:2313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Meyer PN, Fu K, Greiner T, Smith L, Delabie J, Gascoyne R, et al. The stromal cell marker SPARC predicts for survival in patients with diffuse large B-cell lymphoma treated with rituximab. Am J Clin Pathol. 2011;135:54–61.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Abdou AG, Asaad N, Kandil M, Shabaan M, Shams A. Significance of stromal-1 and stromal-2 signatures and biologic prognostic model in diffuse large B-cell lymphoma. Cancer Biol Med. 2017;14:151–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, et al. Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;31:692–700.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Scott DW, Wright GW, Williams PM, Lih C-J, Walsh W, Jaffe ES, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123:1214–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Scott DW, Abrisqueta P, Wright GW, Slack GW, Mottok A, Villa D, et al. New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies. J Clin Oncol. 2017;35:1668–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Scott DW, Mottok A, Ennishi D, Wright GW, Farinha P, Ben-Neriah S, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33:2848–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Clot G, Jares P, Giné E, Navarro A, Royo C, Pinyol M, et al. A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome. Blood. 2018;132:413–22.

  20. 20.

    Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32:1112–8.

    Article  Google Scholar 

  22. 22.

    Murawski N, Pfreundschuh M, Zeynalova S, Poeschel V, Hänel M, Held G, et al. Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL. Ann Oncol 2014;25:1800–6.

    Article  CAS  Google Scholar 

  23. 23.

    Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, et al. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group. J Clin Oncol. 2014;32:4127–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12:1013–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012;13:1250–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Friedrichs B, Nickelsen M, Ziepert M, Altmann B, Haenel M, Viardot A, et al. Doubling rituximab in high-risk patients with aggressive B-cell lymphoma -results of the DENSE-R-MegaCHOEP trial. Br J Haematol. 2019;184:760–8.

  27. 27.

    Swerdlow SH, Campo E, Jaffe ES, Harris NL, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoetic and lymphoid tissues. Lyon, France: IARC Press; 2008.

    Google Scholar 

  28. 28.

    Szczepanowski M, Lange J, Kohler CW, Masque-Soler N, Zimmermann M, Aukema SM, et al. Cell-of-origin classification by gene expression and MYC-rearrangements in diffuse large B-cell lymphoma of children and adolescents. Br J Haematol. 2017;179:116–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Cardesa-Salzmann TM, Colomo L, Gutierrez G, Chan WC, Weisenburger D, Climent F, et al. High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. Haematologica. 2011;96:996–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Masque-Soler N, Szczepanowski M, Kohler CW, Spang R, Klapper W. Molecular classification of mature aggressive B-cell lymphoma using digital multiplexed gene expression on formalin-fixed paraffin-embedded biopsy specimens. Blood. 2013;122:1985–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Klapper W, Szczepanowski M, Burkhardt B, Berger H, Rosolowski M, Bentink S, et al. Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood. 2008;112:1374–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics (Oxf, Engl). 2003;4:249–64.

    Article  Google Scholar 

  33. 33.

    Gautier L, Cope L, Bolstad BM, Irizarry RA. affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33:1–22.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for Cox's proportional hazards model via coordinate descent. J Stat Softw. 2011;39:1–13.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Altenbuchinger M, Schwarzfischer P, Rehberg T, Reinders J, Kohler CW, Gronwald W, et al. Molecular signatures that can be transferred across different omics platforms. Bioinforma. 2017;33:2790.

    Article  CAS  Google Scholar 

  37. 37.

    Horn H, Ziepert M, Wartenberg M, Staiger AM, Barth TFE, Bernd H-W, et al. Different biological risk factors in young poor-prognosis and elderly patients with diffuse large B-cell lymphoma. Leukemia. 2015;29:1564–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Staiger AM, Ziepert M, Horn H, Scott DW, Barth TFE, Bernd H-W, et al. Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the german high-grade non-hodgkin's lymphoma study group. J Clin Oncol. 2017;35:2515–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ott G, Ziepert M, Klapper W, Horn H, Szczepanowski M, Bernd H-W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood. 2010;116:4916–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Brody J, Kohrt H, Marabelle A, Levy R. Active and passive immunotherapy for lymphoma: proving principles and improving results. J Clin Oncol. 2011;29:1864–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Riihijärvi S, Fiskvik I, Taskinen M, Vajavaara H, Tikkala M, Yri O, et al. Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial. Haematologica. 2015;100:238–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Huang WM, Wei YQ, Feng R. The multi-roles of tumor associated macrophages in diffuse large B cell lymphoma. Zhonghua Xue Ye Xue Za Zhi. 2018;39:701–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Marchesi F, Cirillo M, Bianchi A, Gately M, Olimpieri OM, Cerchiara E, et al. High density of CD68+/CD163+ tumour-associated macrophages (M2-TAM) at diagnosis is significantly correlated to unfavorable prognostic factors and to poor clinical outcomes in patients with diffuse large B-cell lymphoma. Hematol Oncol 2015;33:110–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Cai Q-c LiaoH, Lin S-x, Xia Y, Wang X-x, Gao Y, et al. High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma. Med Oncol. 2012;29:2317–22.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ciavarella S, Vegliante MC, Fabbri M, Summa S de, Melle F, Motta G, et al. Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue. Ann. Oncol. 2018;29:2363–70.

  47. 47.

    Altenbuchinger M, Rehberg T, Zacharias HU, Stämmler F, Dettmer K, Weber D, et al. Reference point insensitive molecular data analysis. Bioinforma. 2017;33:219–26.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Thomas Hees, Katja Bräutigam, and Daniela Pumm (Stuttgart), Theodora Nedeva (Würzburg), and Beate Mann and Katja Rillich (Leipzig) for excellent technical assistance.

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to German Ott.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Joint senior authors: German Ott and Rainer Spang.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Staiger, A.M., Altenbuchinger, M., Ziepert, M. et al. A novel lymphoma-associated macrophage interaction signature (LAMIS) provides robust risk prognostication in diffuse large B-cell lymphoma clinical trial cohorts of the DSHNHL. Leukemia 34, 543–552 (2020). https://doi.org/10.1038/s41375-019-0573-y

Download citation

Further reading

Search

Quick links