Advertisement

Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL

Frank Vari, David Arpon, Colm Keane, Mark S. Hertzberg, Dipti Talaulikar, Sanjiv Jain, Qingyan Cui, Erica Han, Josh Tobin, Robert Bird, Donna Cross, Annette Hernandez, Clare Gould, Simone Birch and Maher K. Gandhi

Key points

  • Expansion of PD-1+ CD3-CD56hiCD16-ve NK-cells and PD-L1+ monocytes/macrophages is more prominent in cHL than DLBCL.

  • PD-1 blockade reverses the immune evasion mediated by the interaction of PD-1+ NK-cells and PD-L1+ monocytes/macrophages.

Abstract

Much focus has been on the interaction of PD-L1 on malignant B-cells with PD-1 on effector T-cells in inhibiting anti-lymphoma immunity. We sought to establish the contribution of NK-cells and inhibitory CD163+ monocytes/macrophages in Hodgkin Lymphoma (cHL) and Diffuse Large B-cell Lymphoma (DLBCL). Levels of PD-1 on NK-cells were elevated in cHL relative to DLBCL. Notably, CD3-CD56hiCD16-ve NK-cells had substantially higher PD-1 expression relative to CD3-CD56dimCD16+ cells, and were expanded in blood and tissue, more marked in cHL than DLBCL patients. There was also a raised population of PD-L1 expressing CD163+ monocytes that was more marked in cHL compared to DLBCL patients. The phenotype of NK-cells and monocytes reverted back to normal once therapy (ABVD or R-CHOP) had commenced. Tumor associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in-vitro functional model of TAM-like monocytes suppressed activation of PD-1hi NK-cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pre-therapy cHL and DLBCL patients enhanced CD3-CD56hiCD16-ve NK-cell activation. We describe a hitherto unrecognised immune evasion strategy mediated via skewing towards an exhausted PD-1 enriched CD3-CD56hiCD16-ve NK-cell phenotype. In addition to direct inhibition of NK-cells by the malignant B-cell, suppression of NK-cells can occur indirectly by PD-L1/PD-L2 expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.

  • Submitted July 13, 2017.
  • Accepted February 9, 2018.