Immunotherapy of Melanoma: Targeting Helios in the Tumor Microenvironment for Effector Cell Conversion
Abstract
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 IL2R-STAT5 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2018
- Accession Number
- AD1060432
Entities
People
- Harvey Cantor
Organizations
- Dana–Farber Cancer Institute