T cells are incredibly power cancer-killing immune cells. However, sometimes the hostile tumor environment can ”exhaust” them, rendering them dysfunctional and unable to continue eradicating cancer cells. Understanding the molecular details of T cell exhaustion is fundamental for the development of novel cancer immunotherapy to prevent or reverse this exhaustion state. Two critical protein families—NR4A and TOX—have recently been found to be essential for the development of T cell exhaustion, and deletion of either alleviates T cell exhaustion and improves control of tumors in mouse models of cancer.
In this proposal, Dr. Yang aims to extend these discoveries. Specifically, he seeks to:
- investigate whether disrupting these factors can reverse dysfunction in killer T cells that are already exhausted;
- explore additional methods to inhibit NR4A and TOX with other therapeutic interventions and look for synergistic effects;
- define the molecular mechanisms through which NR4A and TOX impose exhaustion in killer T cells; and
- determine whether NR4A and TOX have similar effects in human killer T cells.
Overall, his work will provide molecular insights into killer T cell exhaustion and the therapeutic potential of NR4A or TOX inhibition, hopefully paving the way for future clinical strategies for humans with cancer.
Projects and Grants
Transcriptional reinforcement of cytolytic T cell responses against solid tumours
La Jolla Institute for Immunology | All Cancers | 2020 | Anjana Rao, Ph.D.
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