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Patterns of immune checkpoint protein expression in MYC-overexpressing aggressive B-cell non-Hodgkin lymphomas

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Abstract

Given the poor prognosis of MYC-overexpressing diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma/high grade B cell lymphoma (BCLU/HGBL), and preclinical data suggesting that MYC may regulate the antitumor immune response, we sought to characterize expression of immune checkpoint proteins on tumor tissue from patients diagnosed with these lymphomas. Immunohistochemical staining for immune checkpoint protein expression was applied to 56 cases of MYC-overexpressing DLBCL and BCLU/HGBL, 35 of which also harbored MYC rearrangement (MYC-R). Analysis revealed both frequent overexpression of immune checkpoint proteins as well as differences in overexpression patterns based upon MYC-R status, with MYC-R cases more likely to overexpress PD-L1 and PD-1 in the tumor microenvironment (50 vs. 15%, p = 0.02 and 32 vs. 5%, p = 0.02, respectively) but less likely to overexpress CTLA-4 and CD80 on tumor cells (34 vs. 71%, p = 0.01 and 34 vs. 81%, p = 0.001, respectively), as compared to cases without MYC-R. These data may suggest a biologic rationale for investigation of the effect of checkpoint inhibitor therapies in these subgroups of MYC-overexpressing DLBCL and BCLU/HGBL.

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References

  1. Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, Horsman DE, Gascoyne RD (2009) MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 114:3533–3537. https://doi.org/10.1182/blood-2009-05-220095

    Article  CAS  PubMed  Google Scholar 

  2. Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, Roman E, Jack A (2010) Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 28:3360–3365. https://doi.org/10.1200/JCO.2009.26.3947

    Article  CAS  PubMed  Google Scholar 

  3. Xu-Monette ZY, Deng Q, Manyam GC et al (2016) Clinical and biologic significance of MYC genetic mutations in de novo diffuse large B-cell lymphoma. Clin Cancer Res 22:3593–3605. https://doi.org/10.1158/1078-0432.CCR-15-2296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kluk MJ, Chapuy B, Sinha P et al (2012) Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas. PLoS ONE 7:e33813. https://doi.org/10.1371/journal.pone.0033813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hu LY, Xu XL, Rao HL et al (2017) Expression and clinical value of programmed cell death-ligand 1 (PD-L1) in diffuse large B cell lymphoma: a retrospective study. Chin J Cancer 36:94. https://doi.org/10.1186/s40880-017-0262-z

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kiyasu J, Miyoshi H, Hirata A et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Casey SC, Baylot V, Felsher DW (2018) The MYC oncogene is a global regulator of the immune response. Blood 131:2007–2015. https://doi.org/10.1182/blood-2017-11-742577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Elbaek MV, Pedersen MO, Breinholt MF et al (2019) PD-L1 expression is low in large B-cell lymphoma with MYC or double-hit translocation. Hematol Oncol 37:375–382. https://doi.org/10.1002/hon.2664

    Article  CAS  PubMed  Google Scholar 

  9. Johnson NA, Slack GW, Savage KJ 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 30:3452–3459. https://doi.org/10.1200/JCO.2011.41.0985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kwon D, Kim S, Kim PJ et al (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

    Article  PubMed  Google Scholar 

  11. Cheson BD, Pfistner B, Juweid ME et al (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586. https://doi.org/10.1200/JCO.2006.09.2403

    Article  PubMed  Google Scholar 

  12. Hans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282. https://doi.org/10.1182/blood-2003-05-1545

    Article  CAS  PubMed  Google Scholar 

  13. Landsburg DJ (2016) Management of patients with MYC-altered lymphomas. Curr Hematol Malig Rep 11:208–217. https://doi.org/10.1007/s11899-016-0320-7

    Article  PubMed  Google Scholar 

  14. Marzec M, Zhang Q, Goradia A et al (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci USA 105:20852–20857. https://doi.org/10.1073/pnas.0810958105

    Article  PubMed  PubMed Central  Google Scholar 

  15. Atsaves V, Tsesmetzis N, Chioureas D et al (2017) PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. Leukemia 31:1633–1637. https://doi.org/10.1038/leu.2017.103

    Article  CAS  PubMed  Google Scholar 

  16. Kowanetz M, Zou W, Gettinger SN et al (2018) Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci USA 115:E10119–E10126. https://doi.org/10.1073/pnas.1802166115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Davis AA, Patel VG (2019) The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer 7:278. https://doi.org/10.1186/s40425-019-0768-9

    Article  PubMed  PubMed Central  Google Scholar 

  18. Casey SC, Tong L, Li Y et al (2016) MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352:227–231. https://doi.org/10.1126/science.aac9935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li L, Sun R, Miao Y et al (2019) PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program. Mod Pathol 32:741–754. https://doi.org/10.1038/s41379-018-0193-5

    Article  CAS  PubMed  Google Scholar 

  20. Valera A, Lopez-Guillermo A, Cardesa-Salzmann T et al (2013) MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica 98:1554–1562. https://doi.org/10.3324/haematol.2013.086173

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This research was funded by philanthropic donations to the Lymphoma Molecular Diagnostics Fund of the Abramson Cancer Center.

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Authors and Affiliations

  1. University of Pennsylvania, Philadelphia, PA, USA

    Daniel J. Landsburg, Alexa Koike, Sunita D. Nasta, Jakub Svoboda, Stephen J. Schuster & Gabriel C. Caponetti

  2. Fox Chase Cancer Center and University of Pennsylvania, Philadelphia, USA

    Mariusz A. Wasik

Authors
  1. Daniel J. Landsburg
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  2. Alexa Koike
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  3. Sunita D. Nasta
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  4. Jakub Svoboda
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  5. Stephen J. Schuster
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  6. Mariusz A. Wasik
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  7. Gabriel C. Caponetti
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Contributions

DJL, SJS, MAW and GCC contributed to the study conception and design. Material preparation, data collection and analysis were performed by DJL, MAW and GCC. The first draft of the manuscript was written by DJL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Daniel J. Landsburg.

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This protocol was approved by the Institutional Review Board of the University of Pennsylvania.

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A waiver of informed consent was granted by the Institutional Review Board of the University of Pennsylvania.

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Landsburg, D.J., Koike, A., Nasta, S.D. et al. Patterns of immune checkpoint protein expression in MYC-overexpressing aggressive B-cell non-Hodgkin lymphomas. Cancer Immunol Immunother 70, 869–874 (2021). https://doi.org/10.1007/s00262-020-02708-3

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  • DOI: https://doi.org/10.1007/s00262-020-02708-3

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