Role of AHR, HIF-1α and IL-27 in T-cell-mediated immunity in Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and remains incurable, largely due to its reliance on a supportive and immunosuppressive tumor microenvironment (TME). Regulatory T cells (Tregs), known for dampening immune responses, play a key role in promoting CLL progression by suppressing anti-tumor immunity. This project investigated the role of the transcription factors AHR and HIF-1α in Tregs during CLL development. Using conditional knockout mice lacking Ahr or Hif1a specifically in Tregs, we found a marked delay in CLL progression, associated with reduced immune checkpoint expression on Tregs and enhanced CD8+ T cell activity. These findings extended to solid tumors, as B16F10 melanoma burden was similarly reduced in knockout mice. Ex vivo studies further confirmed that Tregs lacking AHR or HIF-1α exhibited impaired suppressive function and altered metabolism, highlighting the critical role of these transcription factors in maintaining Treg-mediated immunosuppression. In the second part of the study, we explored the role of Interleukin-27 (IL-27), a cytokine with context-dependent immune functions. Using Eμ-TCL1 and Ebi3-knock out mice, as well as clinical CLL samples, we showed that IL-27 supports anti-tumor immunity by enhancing CD8+ T cell activation and cytotoxicity. IL-27 depletion led to accelerated CLL progression and a more immunosuppressive TME. Notably, IL-27 levels were found to decline during CLL progression in both mouse models and patients. Overall, our results identify AHR and HIF-1α as key regulators of Treg function in CLL and reveal IL-27 as a promising immunotherapeutic target for restoring effective anti-tumor responses.