Session: 622. Lymphomas: Translational–Non-Genetic: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Methods and Results: In this study, we evaluated the role of CD84 in CTCL and, for the first time, reported CD84 as a potential target to reduce immunosuppression through the PD-L1/PD1 axis in CTCL. We found upregulated CD84, CD274 (PD-L1), and PDCD1 (PD1) gene expressions in CTCL patients (n=5) compared to healthy individuals (n=4). We also noted higher CD84 gene expression in SS patients (n=8) than in MF patients (n=6). We next evaluated CD84 expression on the formalin-fixed paraffin-embedded (FFPE) tumor sections derived from SS patients` skin lesions. We noted that CD84 is highly expressed in the TME and co-expressed in Ki67+ Sézary cells. We further evaluated the CD84 expression in immune cell clusters in SS patients and healthy individuals using publicly available single-cell RNA sequencing (scRNA-seq) datasets. We noted a profound CD84 expression in CD4+ T cells and CD163+ M2-like macrophages in SS patients. We also noted a strong correlation between CD84 and CD274 (p=0.0086) and CD84 and PDCD1 (p=0.0002) in SS patients. We next assessed the expressions of CD84, PD-L1 on CD163+ M2-like macrophages, and PD1 on T cell subsets in a coculturing setting with human SS cell line, Hut78, to determine the impact of Sézary cells on these cell compartments in the TME. We observed a significant increase in the percentages of CD163+ M2-like macrophages and CD4+ T cells and elevated CD84, PD-L1, and PD1 expressions on these cells following the coculturing of peripheral blood mononuclear cells (PBMCs) derived from healthy donors (HDs) with Hut78 cells (n=3, *P < 0.05, **P < 0.01). While the percentages of CD8+ T cells were slightly reduced, CD84 and PD1 expressions were elevated in these cells following the coculturing with Hut78 cells (n=3, *P < 0.05, ***P < 0.001). Dysregulation of STAT proteins, particularly STAT3, has been shown in MF/SS (Olszewska et al., 2020). To explore whether Sézary cells regulate STAT3 in CD163+ M2-like macrophages, we assessed pSTAT3 levels in CD163+ M2-like macrophages following the coculturing of HDs PBMCs with Hut78 cells. We found that Hut78 cells significantly increased intracellular pSTAT3 levels in CD163+ M2-like macrophages (n=3, *P < 0.05). Furthermore, we noted the inhibition of STAT signaling using a pan-STAT inhibitor decreased PD-L1 and PD1 expression on CD163+ M2-like macrophages and T-cell subsets, respectively. Notably, we found the stimulation of CD84 signaling with an agonist anti-CD84 mAb enhanced pSTAT3 levels in CD163+ M2-like macrophages, suggesting the STAT pathway might regulate PD-L1 expression in immunosuppressive CD163+ M2-like macrophages through CD84 signaling in SS.
Conclusion: Our preliminary data from this exploratory study indicate that CD84 may be a potential target to reduce immunosuppression in CTCL. Further studies are needed to explore the functions of CD84 as an immune receptor in CTCL TME and its therapeutic potential in CTCL.
Disclosures: Rosen: SLAM BIOTHERAPEUTICS, INC: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Verastem, Inc: Consultancy; Pheromone Bio, Inc: Consultancy; Trillium Therapeutics, Inc: Consultancy; PharmaGene, LLC: Consultancy; Pepromene Bio, Inc: Membership on an entity's Board of Directors or advisory committees; NeoGenomics: Membership on an entity's Board of Directors or advisory committees; Apobiologix/Apotex Inc: Consultancy; Exicure: Consultancy; January Biotech: Current holder of stock options in a privately-held company; Trillium Therapeutics: Current holder of stock options in a privately-held company; Exicure: Current holder of stock options in a privately-held company; Pepromene Bio, Inc: Current holder of stock options in a privately-held company.
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