Tamibarotene

The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs.

We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models.

High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs.

Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

As chronic autoimmune inflammatory diseases, rheumatoid arthritis (RA) and Crohn disease (CD) are closely associated and display a significant positive correlation. However, the underlying mechanisms and disease markers responsible for their cooccurrence remain unknown and have not been systematically studied. Therefore, this study aimed to identify key molecules and pathways commonly involved in both RA and CD through bioinformatic analysis of public sequencing databases. Datasets for RA and CD were downloaded from the GEO database. Overlapping genes were identified using weighted gene co-expression network analysis and differential analysis crossover, and enrichment analysis was conducted for these genes. Protein-protein interaction networks were then constructed using these overlapping genes to identify hub genes. Expression validation and receiver operating characteristic curve validation were performed for these hub genes using different datasets. Additionally, the immune cell correlation, single-cell expression cluster, and the immune cell expression cluster of the core gene were analyzed. Furthermore, upstream shared microRNAs (miRNA) were predicted and a miRNA-gene network was constructed. Finally, drug candidates were analyzed and predicted. These core genes were found to be positively correlated with multiple immune cells that are infiltrated by the disease. Analysis of gene expression clusters revealed that these genes were mostly associated with inflammatory and immune responses. The miRNA-genes network analysis suggested that hsa-miR-31-5p may play an important role in the common mechanism of RA and CD. Finally, tamibarotene, retinoic acid, and benzo[a]pyrene were identified as potential treatment options for patients with both RA and CD. This bioinformatics study has identified ITGB2, LCP2, and PLEK as key diagnostic genes in patients with both RA and CD. The study has further confirmed that inflammation and immune response play a central role in the development of both RA and CD. Interestingly, the study has highlighted hsa-miR-31-5p as a potential key player in the common mechanism of both diseases, representing a new direction in research and a potential therapeutic target. These shared genes, potential mechanisms, and regulatory networks offer new opportunities for further research and may provide hope for future treatment of patients with both RA and CD.