Abstract
Fibrosis represents the end-stage pathology of nearly every form of chronic disease, marked by the accumulation of extracellular matrix (ECM) proteins due to the activity of activated fibroblasts, also known as fibroblasts. This pathological process can affect virtually any organ. Unfortunately, current antifibrotic therapies that selectively target these fibrogenic cells while sparing homeostatic fibroblasts in healthy tissues are limited. During fibrogenesis, specific genes such as the disintegrin metalloprotease ADAM12 and the transcription factor GLI1 become reactivated in fibroblasts. Our research aimed to determine whether specific immunization against endogenous proteins, which are highly expressed in fibrogenic cells but restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. Through in silico epitope prediction, we identified that the activation of genes Adam12 and GLI1 in profibrotic cells results in "self-peptides" that can be exploited for T cell vaccines targeting fibrogenic cells. We demonstrated the efficacy of this vaccination approach in inducing CD8+ T cell responses, which successfully reduced fibroblasts and fibrosis in the liver, lungs and kidneys in mice. Similarly, in pancreatic ductal adenocarcinoma (PDAC), massive intratumoral fibrosis known as desmoplasia is observed. This condition involves the expansion of cancer-associated fibroblasts (CAFs) and a significant increase in ECM. We tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth and a reduction in CAFs and tumor desmoplasia. Additionally, the ADAM12 vaccine led to vascular normalization and reduced tumor hypoxia. In summary, these findings provide proof-of-concept for developing vaccination-based immunotherapies for treating both organ fibrosis and tumor desmoplasia, highlighting the potential of targeting fibrogenic cells through immunization strategies.
Chen, Jing