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 CD163monocytes/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, CD3CD56CD16NK-cells had substantially higher PD-1 expression relative to CD3CD56CD16cells, and were expanded in blood and tissue, more marked in cHL than DLBCL patients. There was also a raised population of PD-L1 expressing CD163monocytes 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-1NK-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 CD3CD56CD16NK-cell activation. We describe a hitherto unrecognised immune evasion strategy mediated via skewing towards an exhausted PD-1 enriched CD3CD56CD16NK-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
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