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M2-like tumor-associated macrophages (TAMs) are the most abundant phenotype that promote the growth of cutaneous T cell lymphoma (CTCL) by inducing immunosuppression. Although PD1/PD-L1blockade has demonstrated efficacy in CTCL, little is known about the effects on tumor-associated macrophages. Here, we report that anti–PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment toward a more pro-inflammatory phenotype. Understanding the mechanisms of macrophage reprogramming will identify novel therapeutic targets to reverse impaired immunity. We used multiplex immunofluorescence staining of lesional skin samples of CTCL patients demonstrating co-localization of PD1 on CD163+ M2 macrophages. Moreover, RNA-seq analysis performed on tissue sections from same CTCL specimens revealed an up-regulation of the TLR, NF-κB and JAK/STAT signaling pathways. To further confirm PD1 expression on M2 TAMs in CTCL, we cultured CD14+ cells from healthy donor-derived peripheral blood in conditioned media (CM) from MyLa cells. We observed macrophage differentiation towards an PD1+ M2 phenotype, with significant CD163, CD206 and PD1 upregulation but not CD80 expression. The TRIF-stimulated NF-κB and JAK/STAT signaling pathways, downstream of both TLR3 and TLR4 were activated in PD1+ M2-like TAMs. Furthermore, our RT-PCR results show significantly elevated IL-10 levels, but decreased IL-1β, CXCL-10 and CXCL-11 compared to control. To determine whether PD1+ M2-like TAMs could be reprogrammed, anti-PD-L1 (durvalumab) and lenalidomide were used for treatment of MyLa-conditioned media induced human peripheral blood monocyte-derived PD1+ M2-like TAMs. The results show that anti-PD-L1 and lenalidomide synergistically increased IL-1β, CXCL-10, and CXCL-11 expression, but significantly decreased IL-10 level compared with the untreated control in vitro through ablation of TLR3, TLR4 and the downstream signaling pathways, which was linked with functional changes in phagocytic activity and cell migration. [ABSTRACT FROM AUTHOR]