PD-L1 and PD-L2 Are Differentially Expressed by Macrophages or Tumor Cells in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

As checkpoint molecules' inhibition may represent a therapeutic option in relapsing cases, we assessed programmed death ligands' (PD-L1/PD-L2) expression in a series of 29 primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) cases. Double immunostaining for either PD-L1 or PD-L2 was associated either with PAX5 staining to evaluate tumor cells or with CD68 or CD163 staining for macrophages. The microenvironment of PCDLBCL-LT was characterized by immunostainings for CD3 (tumor-infiltrating lymphocytes), FOXP3 (regulatory T cells), programmed cell death-1, and CD33 (myeloid-derived suppressor cells). The 9p24.1 locus encoding for PD-L1/PD-L2 was evaluated by fluorescence in situ hybridization. A PD-L1 expression was observed in all cases. However, double staining with PD-L1/PAX5 identified only 1 case harboring PD-L1 expression by tumor cells. All cases displayed PD-L1 expression by numerous immune cells, characterized as CD68 CD163 M2 macrophages. A normal fluorescence in situ hybridization pattern was observed in 21 of 26 cases. Three cases (11.5%) harbored a low polysomy status including the case with PD-L1 expression by tumor cells. Interestingly, 2 cases (7.7%) exhibited a PD-L1/PD-L2 locus break-apart pattern, and PD-L2 expression by tumor cells was observed. PD-L2 expression by tumor cells was not observed in the 24 cases without 9p24.1 rearrangement. Treating patients with relapsing PCDLBCL-LT by using immune checkpoint inhibitors may have an indirect effect through immune cells, except in rare cases with 9p24.1 rearrangement leading to PD-L2 expression by tumor cells. Reprogramming tumor-associated macrophages with anticancer therapies is appealing in such lymphoma subtypes wherein M2 macrophages represent the majority of immune cells.