Abstract IA-027: Dysregulated metabolic and immune pathways underlying radiation fibrosis and lymphedema

Abstract

Abstract Introduction: Radiation fibrosis (RF) is a long-term complication affecting up to ~1/3 of all patients post treatment, characterized by excess extracellular matrix (ECM), decreased tissue elasticity, leading to potential loss of organ function. The regulation of ECM production and degradation is complex, mediated through a myriad of cytokines including TGFB, and environmental conditions such as hypoxia. Currently, this is an irreversible and untreatable condition, affecting up to 6M cancer survivors in the US. Lymphedema is another inflammatory condition, which also has no effective treatments and is irreversible. In the literature, there is a strong suggestion that metabolic dysregulation might be an underlying process affecting both RF and lymphedema; hence, this avenue of investigation was undertaken for both conditions. Materials & Methods: Mouse models were established for both RF and lymphedema, using the C3H and C57/Bl6 mice; respectively. Genome-wide transcriptomic sequencing analyses were undertaken for both conditions, using human and mouse tissues. For the lymphedema experiments, single-cell RNA-sequencing (scRNA-seq) was performed, to identify the different cell types in the murine lymphedematous fluid. Finally, a pharmacogenomics strategy was undertaken using the CMAP and L1000 databases for the RF and lymphedema studies; respectively, to identify novel compounds or drugs, which can treat these conditions. Results: For both RF and lymphedema studies, metabolic dysregulation, and specifically, downregulation of PPAR signaling and fatty acid oxidation (FAO) were key pathways driving the production and reducing the degradation of collagen, the predominant component of the ECM. Conversely, upregulation of PPAR signaling reduced transcription of key ECM genes for both conditions. In the RF studies, CD36, a membrane transporter of long chain fatty acids, was discovered to play a critical role in regulating the trafficking of collagen and lysosomal degradation. ScRNA-seq of murine lymph fluid identified 8 cell clusters with T helper 17 (Th17) cells being the dominant population (24%). Furthermore, these immune cells also demonstrated downregulation of PPAR signaling, suggesting that this process was universal at both the bulk, and single cell level. Pharmacogenomics analyses identified caffeic acid or its derivate CAPE (caffeic acid phenethyl ester) to be compounds, which can be systemically administered, and reduced cellular proliferation and fibrosis in pre-clinical models for both conditions. Vorinostat however, was even more effective in reducing these processes in lymphedema conditions. Conclusion: For the first time, we have demonstrated that metabolic dysregulation with downregulation of PPAR signaling and FAO as major contributors to both RF and lymphedema. These processes can be mitigated pharmacologically, by using agents such as CAPE or Vorinostat, indicating that these heretofore-untreatable toxicities of radiation therapy can be reversed using such strategies. Citation Format: Fei-Fei Liu. Dysregulated metabolic and immune pathways underlying radiation fibrosis and lymphedema [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-027.