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Mass cytometry of Hodgkin lymphoma reveals a CD4+ exhausted T-effector and T-regulatory cell rich microenvironment

Fathima Zumla Cader, Ron C.J. Schackmann, Xihao Hu, Kirsty Wienand, Robert Redd, Bjoern Chapuy, Jing Ouyang, Nicole Paul, Evisa Gjini, Mikel Lipschitz, Philippe Armand, David Wu, Jonathan R. Fromm, Donna Neuberg, X. Shirley Liu, Scott J. Rodig and Margaret A. Shipp

Key points

  • Newly diagnosed primary cHLs have a concomitant increase in CD4+ Th1-polarized Tregs and differentiated T-effectors.

  • Primary cHLs exhibit two major complementary bases of immunosuppression - likely exhausted PD-1+ Th1 effectors and active PD-1- Th1 Tregs.

Abstract

In classical Hodgkin lymphoma (cHL), the host anti-tumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of the PD-1 ligands and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T-effectors (Teff). However, durable responses are observed in patients with β2M/MHC class I loss on HRS cells, raising the possibility of non-CD8+ T cell-mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry (CyTOF) panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4+ T-cell rich with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of Th1-polarized Teff and regulatory T cells (Treg). The cHL Th1 Tregs expressed little or no PD-1 while the Th1 Teffs were PD-1+. The differential PD-1 expression and likely functional Th1-polarized CD4+ Tregs and exhausted Teff may represent complementary mechanisms of immunosuppression in cHL.

  • Submitted April 10, 2018.
  • Accepted June 2, 2018.