Inactivation of FOXO1 induces T follicular cell polarization and involves angioimmunoblastic T cell lymphoma

Objective: Angioimmunoblastic T cell lymphoma (AITL) is an aggressive form of non-Hodgkin lymphoma derived from matureT cells. However, the underlying pathogenesis of AITL remains unresolved. We aimed to explore the role of FOXO1-mediatedsignaling in the tumorigenesis and progression of AITL. Methods: FOXO1 expression was assessed using immunohistochemistry on a total of 46 AITL tissue samples. Retrovirusesencoding FOXO1 shRNA were used to knockdown FOXO1 expression in CD4+ T cells. Flow cytometric assays analyzed theproliferation and survival of FOXO1 knockdown CD4+ T cells. Furthermore, we performed adoptive T-cell transfer experimentsto identify whether inactivation of FOXO1 induced neoplastic follicular-helper T (Tfh) cell polarization and function. Results: Patients with low FOXO1 protein levels were prone to have an advanced tumor stage (P = 0.049), higher ECOG ps (P =0.024), the presence of bone marrow invasion (P = 0.000), and higher IPI (P = 0.035). Additionally, the survival rates of patients inthe FOXO1 high-expression group were significantly better than those in the FOXO1 low-expression group (χ2 = 5.346, P =0.021). We also observed that inactivation of FOXO1 increased CD4+ T cell proliferation and altered the survival and cell-cycleprogression of CD4+ T cells. Finally, we confirmed that inactivation of FOXO1 induces Tfh cell programing and function. Conclusions: Inactivation of FOXO1 in AITL plays a key role in the tumorigenesis and progression of AITL. We propose thatFOXO1 expression could be a useful prognostic marker in AITL patients to predict poor survival, and to design appropriatetherapeutic strategies. Cite this article as: Xu M, Wang F, Chen H, Liu L, Liu W, Yang Y, et al.Inactivation of FOXO1 induces T follicular cell polarization and involvesangioimmunoblastic T cell lymphoma. Cancer Biol Med. 2019; 16: 743-55.doi: 10.20892/j.issn.2095-3941.2019.0115