Immunotherapy of Melanoma: Targeting Helios in the Tumor Microenvironment for Effector Cell Conversion
[Technical Report, Final Report]
Dana-Farber Cancer Institute
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Accumulation of activated and suppressive regulatory T cells Treg within the tumor microenvironment TME is a major obstacle to the development of efficient anti-tumor immunity. Although Treg depletion can enhance anti-tumor immune responses, autoimmune sequelae can complicate this approach. To analyze the impact of transcription factor Helios on FoxP3 CD4 Treg in lymphoid tissues, we determined that Helios activates the IL2RSTAT5 pathway to enhance FoxP3 expression and maintain Treg suppressive activity. The observation that Helios-deficient Treg enhancement of anti-tumor immunity may reflect conversion of unstable Helios Treg into T effector cells Teff within tumors was tested by inducing Treg lineage instability to promote anti-tumor immunity. During the first year of funding, we performed transcriptome analysis of intratumoral Treg, which revealed that Helios deficient intratumoral Treg adopt a genetic program that is typical of effector Th1 and Th2 cells. We also tested the feasibility of enhancement of anti-tumor immune responses by Treg conversion by targeting IL-23R using antibodies or genetic mouse models. Hypothesis driven analysis of the mechanism of Treg reprogramming upon blockade of IL-23 signaling is currently underway. These findings are consistent with our hypothesis that antibody-based approaches to reprogram tumor-infiltrating Treg into T effector cells represent a potential immunotherapeutic approach to the treatment of melanoma.
- Medicine and Medical Research