Targeting the PSGL-1 Immune Checkpoint to Promote Melanoma Tumor Control
Abstract
The Peer Reviewed Cancer Research Program Topic to be addressed by this application is melanoma skin cancer. Human cancers including melanoma are associated with impaired and ineffective immune system responses. In melanoma patients, T cells of the immune system whose function is to kill tumor cells are suppressed. With their failure to destroy these tumors, the cancer cells can spread throughout the body and can then be lethal. Many molecules can function in suppressing T cells, and manipulating these pathways has shown that T cells can be rejuvenated to destroy tumors. In particular, immune system inhibitory proteins are found on T cells in melanoma tumors. Individually blocking these inhibitory receptors with antibodies have been Food and Drug Administration-approved for treatment of this disease. Despite remarkable efficacy in some patients, the majority do not respond. Our studies using a virus infection model in which T cells become inhibited have shown an important role for the protein, PSGL-1 (P-selectin glycoprotein-1), as an inhibitory receptor on the surface of T cells. Mice lacking PSGL-1 showed a restoration of function in T cells responding to the virus, and these cells were better at killing infected cells and melanoma tumors. Most importantly, in the absence of PSGL-1, several immune inhibitory receptors were no longer present at high levels. We now propose to further test how PSGL-1 plays an immune inhibitory role in a mouse melanoma model that replicates many facets of the human cancer. We identified high levels of PSGL-1 on T cells that were suppressed at the site of skin cancer and on other immune cells that can regulate the activity of these T cells. The goal of this work is to identify the contributions of PSGL-1 to the functions of various immune cells in the tumor and to determine whether blocking PSGL-1 can be used as a therapy to restore function in T cells and cure melanoma. As the Principal Investigator in the proposed project, my career goal is to establish a laboratory to investigate T cell exhaustion mechanisms in melanoma cancer progression. The goal of the proposed research is to determine how and when P-selectin glycoprotein ligand-1 (PSGL-1) signaling inhibits anti-tumor T cells during melanoma tumor development. My future long-term goal in the laboratory is to translate my preclinical studies to investigate T cell exhaustion mechanisms in patient melanoma tumor clinical samples. Furthermore, this funding opportunity will facilitate my entry into this research field by helping me develop research expertise paired with a specific career development plan to help ensure my long-term success as a cancer immunology researcher. This work will test the prediction that PSGl-1 could be an effective therapy for patients diagnosed with melanoma and potentially other cancers of the skin that are less aggressive. The treatment will help melanoma patients by boosting their immune system function to be more effective in eradicating their tumors. In doing so, this treatment could also reduce the probability of a reoccurrence of melanoma by generating a population of T cells that were trained during the immune response to kill the tumors and provide a reservoir of cells that can prevent a new cancer from being established. As with the other therapies that block immune inhibitory receptors found on T cells, it is expected that there will be side effects that are associated with the improved immune responses. However, the extent of side effects will not be known until testing in clinical trials. Although it has taken more than two decades to approve the therapies that target the inhibitory receptors CTLA-4 and PD-1 on T cells, it is expected that new therapeutic treatments will take less time. We are proposing different strategies to inhibit PSGL-1, and the effects that we observe with each strategy will advance our understanding of how PSGL-1 can alter the functions of various immun
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810738
Entities
People
- Roberto Tinoco
Organizations
- Naval Information Warfare Center Pacific
- United States Army