Background/Purpose: Systemic sclerosis (SSc) is a progressive, chronic multi-system disorder of unknown etiology that is characterized by immune dysfunction, fibrosis, and loss of dermal white adipose tissue (DWAT), which is an early event in SSc that precedes the onset of skin fibrosis. Despite advances in disease management, the overall prognosis for SSc remains significantly worse than for other rheumatic diseases. While cooperative interactions between macrophages (MØs) and fibroblasts have been implicated in disease pathogenesis, no therapies that specifically target pathological MØs are in current clinical use for SSc.

Methods: Because our prior studies demonstrate a critical role for CD206high MØs in SSc pathology, we developed a novel therapeutic approach to eliminate these cells using chimeric antigen receptor (CAR) T cells. CAR T cell efficacy was tested in the bleomycin (BLM) mouse model of SSc. BLM was delivered via osmotic pump, and a single dose of anti-CD206 or control CAR T cells was administered systemically via tail vein injection 7 days post-initiation of BLM to assess effects on established dermal pathology. Skin tissues were fixed and paraffin-embedded for single cell RNA-seq (scRNA-seq) and spatial transcriptomic analyses, and for quantification of adipose and dermal thickness by H&E. An in vitro co-culture model system was developed to assess the mechanisms by which CD206high MØs mediate SSc pathology, and antibody blockade studies were performed to identify the MØ-derived soluble mediators that contribute to skin disease pathogenesis.

Results: We now show that CAR T cell-mediated elimination of CD206high MØs to BLM mice resulted in restoration of DWAT to levels observed in mice not treated with BLM. Notably, administration of control CAR T cells failed to rescue DWAT loss. scRNA-seq and spatial transcriptomics analyses demonstrated anti-CD206 CAR T treatment increases mature adipocyte populations and alters representation of extracellular matrix (ECM)-secreting fibroblast and inflammatory myeloid subsets. In vitro modeling demonstrated that CD206high MØs redirect lineage commitment of adipocyte stem cells (ADSCs) from adipocytes toward fibroblasts in a mechanism dependent, at least in part, on IL-6 receptor engagement.

Conclusion: Our new findings demonstrate that anti-CD206 CAR T cell therapy significantly attenuates dermal pathology in SSc through restoration of DWAT, implicating a novel function for MØs in the regulation of early fibrotic disease. In vitro mechanistic studies are supportive of a model in which CD206high macrophages provide signals mediated by IL-6 that alter ADSC commitment from adipogenic to fibrogenic. Activated fibroblasts then secrete excessive extracellular matrix (ECM), culminating in fibrotic disease. Collectively, our results suggest MØ-targeted therapies may be effective in ameliorating SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-cd206-car-t-cell-immunotherapy-mitigates-dermal-pathology-in-systemic-sclerosis/