Exploring the Role of Neuritin in Regulatory T-Cell-Mediated Immune Suppression and Testing Its Value as a Novel Target for Ovarian Cancer Immunotherapy
Abstract
Rationale: Ovarian cancer is deadly and difficult to detect before tumors progress to an advanced stage. While many patients respond to current therapies, ovarian cancer often reappears, and survival rates remain low (with less than 30% of patients surviving for five years). For these reasons, effective and lasting treatment of ovarian cancer remains a formidable challenge among past and present members of the military service as well as the general population. While the immune system can both detect cancer cells and execute potentially devastating tumor-killing functions, in many cancers it fails to control the growth of tumors. Among the factors that suppress effective anti-ovarian cancer immune responses are a population of T cells known to inhibit the activity of other immune cells. In cancer patients, these so-called “regulatory” T cells (or “Tregs”) are increased in number and interfere with the killing of ovarian tumor by other killer immune cells. Work in mouse tumor models strongly suggests that eliminating or inhibiting Tregs can unleash the tumor-killing potential of the immune system and improve survival. The list of suitable target molecules for such Treg-sabotaging therapies, however, remains limited, and markers highly expressed by Treg subsets that preferentially suppress anti-tumor immunity are only beginning to be identified and studied. Thus, by devising new approaches for overcoming the immune suppression imposed by Tregs in ovarian cancer patients we seek to overcome a critical problem in the field. In previous work, we found that a molecule traditionally studied in nerve cells (called “neuritin”) was surprisingly made by Tregs, but not other immune cells. Additionally, Tregs recovered from mouse tumors expressed high levels of neuritin. Experiments studying neuritin-deficient mice revealed that neuritin is critical for the ability of Tregs to suppress immune responses. Importantly, we also found that without neuritin, Tregs fail to express genes thought to be necessary for their accumulation and suppressive function within tumors. While the mechanism for neuritin-mediated Treg function remains unknown, our preliminary results led us to suspect that neuritin equips Tregs with the traits needed to infiltrate ovarian tumors and suppress the anti-tumor response there, and, blocking neuritin should have a potent anti-tumor effect. We will test these notions in our proposed studies and, in so doing, we aim to gain new insights into potential immunotherapy treatments likely to be effective against ovarian cancer. Objective: The goals of this study are to reveal how neuritin supports a population of Treg cells that interferes with the killing of ovarian cancer cells by the immune system; determine if therapies that block neuritin activity can slow or stop tumor growth in mice; and establish whether or not such therapies are likely to improve survival in human patients. Approach: With the support of an OCRP Pilot Award, we will determine how neuritin expression affects the functional potency of Tregs, their cellular fitness, and the genes expressed in these important suppressor cells. These studies will involve in vitro assays of Treg function. We also propose to study the consequences of genetically altering levels of neuritin expression in mice with ovarian cancer. To this end we will monitor ovarian cancer cells in normal mice as well as mutant mice either lacking neuritin or mice engineered to express excessive amounts of this newly identified driver of Treg suppressive function. We will monitor the rate and spread of tumor growth, mouse survival, and the effectiveness of the anti-tumor immune response in the presence of varying neuritin levels. We will also block neuritin activity with an antibody to potentially stunt tumor growth in this model, therapeutically, to determine whether anti-neuritin therapies will improve the anti-tumor immune response. In order to shed light on how neuritin specific
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810128
Entities
People
- Joseph Barbi
Organizations
- United States Army