Posted: Monday, December 12, 2022
According to Patrizia Mondello, MD, PhD, MSc, of the Mayo Clinic, Rochester, Minnesota, and colleagues, approximately 20% of patients with follicular lymphoma have early relapse with a poor prognosis. These investigators identified three distinct molecular clusters—including IRF4—that characterize an unfavorable tumor microenvironment and poor outcome in this patient population. These findings were presented during the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 70).
“Collectively, we found that follicular lymphomas with IRF4-high expression are associated with a suppressive tumor microenvironment, and selective IRF4 silencing restores antilymphoma T-cell immunity,” concluded the study authors. “Further investigation is warranted to identify the mechanisms by which IRF4 controls tumor immunity to develop precision therapies for this unfavorable population.”
IRF4 is a master regulator and plays a crucial role in terminal B-cell differentiation. The RNA-sequencing, whole-exome sequencing, and mass cytometry data of 88 patients with newly diagnosed follicular lymphoma were integrated to investigate the impact of IRF4 on immune signatures in the tumor microenvironment.
Follicular lymphomas exhibiting high IRF4 expression demonstrated a significant enrichment in M1 (P = .027) and M2 (P < .001) macrophages, T-regulatory cells (P < .001), and CD4-positive T cells (P < .001) compared with low IRF4 expression. Additionally, RNA sequencing of these tumors revealed upregulation of 3,448 genes and downregulation of 2,907 genes when stratified by IRF4 status. Furthermore, lymphomas with high IRF4 expression appeared to develop mutations more frequently than those with low IRFA expression.
NF-kB luciferase activity did not seem to be altered by the selective inhibition of IRF4. TMD8 and SUDHL2 cells transfected with small interference RNA IRF4 and CD4-positive T cells were co-cultured to elucidate whether IRF4 silencing triggers antilymphoma immunity. As a result, cell viability was decreased; silencing of IRF4 in lymphoma cells doubled the number of T follicular helper cells and halved the number of T-regulatory cells.
Disclosure: For full disclosures of the study authors, visit ash.confex.com.