Neuritin-Mediated Reprogramming of Myeloid Cell Populations: Mechanisms of Immune Suppression and Roads to Improve Therapy in Ovarian Cancer
Abstract
Background: In order for the immune system to properly defend against infections, its impressive destructive power must be controlled. Failure to do so can lead to the damage of healthy tissues by excessive or self-directed immune responses. Among the mechanisms of immune regulation are the so-called regulatory T cells (or Tregs). Through their characteristic ability to suppress the activity of other immune cells, Tregs provide this necessary immune restraint. Unfortunately, however, Tregs can also accumulate in cancer patients and inhibit desirable anti- tumor immune responses. Depleting Tregs or disrupting their function can improve the tumor-killing capacity of the immune system. However, molecules and processes uniquely important for the survival and function of Tregs (and not other immune cells with beneficial anti-tumor properties) must be first identified and characterized in order to exploit them as potential immunotherapy targets. Unexpectedly, we and others have found that Tregs express high levels of a molecule previously studied in the nervous system called neuritin. Importantly, this factor has been reported to upregulated in ovarian tumors. We show that neuritin is important for Treg function in diverse animal models. In these studies, mice genetically lacking neuritin expression were found to contain defective Tregs, and these mice displayed both enhanced activation of tumor-killing immune cells and stunted tumor growth. While the mechanism responsible for neuritin’s pro-Treg and pro-tumor effects remains unknown, our findings suggest that (1) neuritin is expressed by a highly suppressive subset of Tregs prevalent in ovarian cancer and (2) neuritin interferes with a well-known pathway of immune cell activation. Summary of Pilot Study Findings: In earlier studies, we found that neuritin is expressed by Tregs and is important for both the suppressive behavior of these cells and the progression of aggressive tumors in mice. Neuritin is therefore a potential target for new anti-cancer therapies intended to boost anti-tumor immunity (such as anti-neuritin blocking antibodies). However, exactly how neuritin accomplishes these effects remains unknown and must be understood before it can be effectively exploited as a therapeutic target. Findings from a pilot study supported by the DOD’s OCRP suggest that (1) neuritin is expressed by a highly suppressive subset of Tregs prevalent in ovarian cancer (so called eTregs); (2) genetic and antibody mediated blockade of neuritin dramatically slows tumor growth in an aggressive mouse model of ovarian cancer; and (3) neuritin interferes with a well-known pathway of immune cell activation at the heart of an experimental class of immunotherapy agent currently being tested in ovarian cancer clinical trials (i.e., CD40 agonists). New Insights: The signaling pathway triggered by the interaction of the cell surface markers CD40 and CD40Ligand (CD40L) is known to initiate immune responses and activate cells with tumor-killing abilities. Artificial stimulation of CD40-CD40L signaling is even being explored as a means to boost anti-tumor immunity in cancer patients. Interestingly, in preliminary studies, we found that overexpression or supplementation with recombinant neuritin could favor immune suppression by Tregs and suppression-favoring phenotypes in APCs instead of immune activation, even in the face of robust CD40-CD40L activation. On the other hand, when suppressor cells are unable to produce neuritin, they fail to function upon activation of this pathway. Based on these findings, we hypothesize that neuritin drastically alters the outcome of CD40-CD40L signaling to suppress immune responses and therefore it opposes the tumor-fighting potential of CD40-activating cancer therapies. Study Goals: We propose to determine how neuritin contributes to the suppressive function of Tregs and the failure of anti-tumor immunity in the context of ovarian cancer
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310266
Entities
People
- Joseph Barbi
Organizations
- United States Army