Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma

J Clin Oncol. 2018 Apr 1;36(10):942-950. doi: 10.1200/JCO.2017.77.3994. Epub 2018 Feb 2.


Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.

Trial registration: NCT02181738.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation
  • Antineoplastic Agents, Immunological / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / biosynthesis*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Chromosomes, Human, Pair 9
  • Cohort Studies
  • Histocompatibility Antigens Class II / biosynthesis*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Hodgkin Disease / drug therapy*
  • Hodgkin Disease / genetics
  • Hodgkin Disease / immunology*
  • Hodgkin Disease / pathology
  • Humans
  • Nivolumab / therapeutic use*
  • Predictive Value of Tests
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / biosynthesis
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Progression-Free Survival
  • Reed-Sternberg Cells / drug effects
  • Reed-Sternberg Cells / immunology
  • Reed-Sternberg Cells / pathology
  • Treatment Outcome
  • beta 2-Microglobulin / biosynthesis
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / immunology


  • Antineoplastic Agents, Immunological
  • B2M protein, human
  • B7-H1 Antigen
  • CD274 protein, human
  • Histocompatibility Antigens Class II
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • beta 2-Microglobulin
  • Nivolumab

Associated data