The Importance of NKG2D Signaling-Induced IL-24 Secretion by Tumor-Specific CD8+ T Cells
Abstract
Fiscal Year 2022 (FY22) Melanoma Research Program (MRP) Focus Area: This proposal is responsive to the FY22 MRP challenge statement in that inducing strong tumor immunity in a patient has the potential to inhibit the emergence from tumor dormancy and the development of metastases. The primary FY22 MRP Focus Area this proposal addresses is to identify how the tumor microenvironment (immune) impacts tumor progression and/or dormancy. Background: Although highly treatable at early stages, once melanoma has spread to distant sites, the survival rate is low. Clearly additional treatment strategies are needed. Recent successes, particularly in melanoma patients, demonstrate the power of using the immune system clinically to destroy cancer. However, this treatment is ineffective in most patients. Our goal is to move forward continued research into how to make a patient’s own immune system destroy their melanoma. One protein on immune cells that we know has an important role in tumor control is called NKG2D. Like NKG2D, a subset of immune cells called CD8+ T cells play an essential role as well. In addition, CD8+ T cells also express NKG2D, along with the proteins that interact with NKG2D to induce tumor cell killing from the cells. The expression of these NKG2D-interacting proteins by CD8+ T cells has largely been ignored by the scientific community. Our preliminary data demonstrate that mouse CD8+ T cells that express these proteins secrete significantly greater amounts of a protein called interleukin-24 (IL-24) compared with those that do not express these proteins. IL-24 has been shown to be able to cause the death of melanoma cells. However, there are major gaps in knowledge about IL-24, including how its production is regulated and the mechanisms by which it performs its biological functions. Objective: To determine if NKG2D is critical in making CD8+ T cells that make IL-24, which have enhanced melanoma-killing properties. Specific Aims Aim 1: Determine how NKG2D induces IL-24 production by mouse CD8+ T cells. Aim 2: Determine the importance of IL-24 production in melanoma control in mouse tumor models. Aim 3: Determine if NKG2D generates human CD8+ T cells that secrete IL-24. Innovation: Although there has been intense interest in using IL-24 clinically, there are major gaps in knowledge about this protein, including how its production is regulated and the mechanisms by which it performs its biological functions. The goal of the work proposed in this IDEA Award application is to begin to fill in these knowledge gaps and determine whether further study into NKG2D-induced IL-24 production by anti-melanoma CD8+ T cells is warranted. Impact: This proposal involves preclinical animal studies and human cell culture studies aimed at increasing therapy options for melanoma. These studies will provide the proof of principle needed to perform larger studies investigating the potential of targeting NKG2D in metastatic melanoma patients to make IL-24-secreting CD8+ T cells that are better killers of melanoma cells. United States active duty and Veteran populations are at an increased risk of melanoma due to the nature of their duties. This makes novel ways of preventing and treating this disease a priority for the military.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310630
Entities
People
- Mary A Markiewicz
Organizations
- United States Army
- University of Kansas Medical Center