Project 461659

Central to immune alterations in the tumor microenvironment (TME) that facilitate tumor growth is the functional attenuation (exhaustion) of CD8 T cells. As a result, restoring function to CD8 T cells so that they can eliminate tumors is currently a main goal of cancer therapy. The underlying mechanisms that promote and sustain T cell exhaustion and how these signals are molecularly communicated from the TME and translated by T cells to adjust their transcriptional programming is a major question in tumor biology and therapy. We have discovered Interferon Regulatory Factor 2 (IRF2) as a central regulator of T cell exhaustion in cancer, balancing inflammatory signals form the TME with functional suppression of anti-tumor T cell activity. Deletion of IRF2 in CD8 T cells prevents T cell exhaustion in the otherwise suppressive TME to enable long-term tumor control, increased responsiveness to immune checkpoint blockade and provides a potential target to engineer T cells for adoptive immunotherapy. Since chronic inflammatory signaling and immunosuppression are hallmarks of many cancer types and fundamental to the outcome of many therapeutic responses, we propose that a better understanding of how IRF2 tunes TME signals to inhibit CD8 T cell immunity is critical for the design of therapies to re-establish immune control and potentially eliminate a wide-array of cancers.