Immunotherapy of Melanoma: Targeting Helios in the Tumor Microenvironment for Effector Cell Conversion
Abstract
This proposal combines studies that are applicable to two current Peer Reviewed Cancer Research Program Topic Areas: Immunotherapy and Melanoma. Although immunotherapy has become a standard therapeutic modality for melanoma and other cancers, approaches that target a subpopulation of immune cells, termed regulatory T cells, have not been directly explored. Previous studies have shown that although immune cells capable of responding specifically to tumors are present during tumor development and growth, these cells are not always able to eliminate malignant cells. These impaired responses reflect, in part, the suppressive activity of regulatory T cells (Treg). Current clinical approaches that deplete or block Treg have shown some clinical efficacy but often carry the risk of side events that are generally autoimmune in nature. Our studies focus on a unique subpopulation of Treg, termed FoxP3+ CD4+ Treg, and on understanding how these cells might be used to modulate the immune response to stimulate anti-tumor immunity. Recent studies have shown that expression of a transcription factor called Helios is essential for Treg stability in the face of inflammatory responses like those found during the course of melanoma tumor growth. Here we study the impact of inhibiting Helios expression within CD4 Treg on the induction of an unstable Treg phenotype and conversion of intratumoral Treg into T effector cells that may kill tumor cells. These findings suggest that antibody-based targeting of Helios may represent a novel and effective approach to immunotherapy of melanoma. The development of new agents with potent anti-tumor activity and low toxicity represents a potential advance in cancer immunotherapy for military personnel and the general population. Military personnel are especially vulnerable to melanoma due to extended exposure to the harmful effects of ultraviolet (UV) radiation experienced during deployment to regions of the world, like Afghanistan and Iraq. While fair-skinned individuals with less pigment or melanin are particularly susceptible to damage from UV radiation, melanoma also develops in military personnel of many complexions, including Hispanics and blacks. Military service in these geographic regions as well as at high elevations increases the risk for melanoma. Military personnel are therefore at a somewhat higher risk. Identification of Helios as an important target for manipulation of the Treg response has opened new avenues of therapy. The proposed studies are intended to define new and effective potential therapeutic approaches to melanoma using immunotherapy-based strategies that may form the foundation of future clinical approaches. We believe that this approach has the potential to achieve a clinically relevant outcome at the end of the 2-year funding period.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710387
Entities
People
- Harvey Cantor
Organizations
- Dana–Farber Cancer Institute
- United States Army