Abstract 2759: Reprogramming of PD1+ M2-like tumor-associated macrophages with anti-PD-L1 and Lenalidomide in cutaneous T cell lymphoma

M2-like tumor-associated macrophages (TAMs) are abundant and influence cutaneous T cell lymphoma (CTCL) development by inducing immunosuppression. Although it is well established that depletion of M2-like TAMs delays CTCL development, little is known about the underlying mechanisms that shape programmed cell death 1+ (PD1+) M2-like TAMs phenotype in CTCL. Here we identified PD1+ M2-like TAMs accumulated in CTCL lesional skin. Moreover, RNA-seq analysis of human CTCL tissues revealed an up-regulation of the TLR/NF-κB and JAK/STAT signaling pathways. In vitro, PD1+ TAMs exhibited an M2-like profile, with a significant increase in the expression of CD163, CD206, and IL-10, and a clear decrease in the expression of CD80, IL-1β, CXCL-10, and CXCL-11, and the activation of TLR/NF-κB and JAK/STAT signaling pathways. 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 reshaped M2-like TAMs to M1-like TAMs in vitro through ablation of the TLR/NF-κB and JAK/STAT signaling pathways, which was linked with functional changes in phagocytic activity and cell migration. In conclusion, TLR/NF-κB and JAK/STAT signaling pathways may drive PD1+ M2-like TAMs programming in the CTCL tumor microenvironment, anti-PD-L1 and lenalidomide may reshape PD1+ M2-like TAMs and induce functional changes through ablation of these specific pathways in CTCL. Corresponding author: Christiane Querfeld, MD, PhD. Div. of Dermatology and Beckman Research Institute, City of Hope. 1500 E. Duarte Road, Duarte, CA 91010. Email: cquerfeld@coh.org Phone: 626-634-4436 Fax: 626-218-6190 Citation Format: Zhen Han1,5, Chingyu Su1,5, Xiwei Wu2,5, Hanjun Qin2,5, Steven T. Rosen3,5, Christiane Querfeld1,3,4,5. Reprogramming of PD1+ M2-like tumor-associated macrophages with anti-PD-L1 and Lenalidomide in cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2759.