Susan M. Kaech, PhD, CRI CLIP Investigator Salk Institute for Biological Studies Area of Research: All Cancers Dr. Kaech’s proposal builds on her recent discovery that the T cell signaling protein kinase C (PKC)-theta can prevent complete T cell exhaustion, while a related protein, PKC-eta, hastens T cells exhaustion. In this proposal, Dr. Kaech will explore this switch from the ‘good PKC-theta’ to the ‘bad PKC-eta,’ to understand the differences in the molecules that the PKCs control in anti-tumor T cells. Immunotherapy encompasses fantastically successful cancer therapies including immune checkpoint blockade, chimeric antigen receptor T cells (CAR-T), and adoptive cell transfer therapy (ACT). These therapies all work by providing a powerful CD8+ T cell response to specifically eliminate cancerous cells. While T cells normally protect us from cancer effectively, tumors can form when T cell response fails. This loss of protection is called T cell exhaustion, and it occurs when T cells have been battling cancer cells for too long. Fundamentally, every immunotherapy aims to restore a population of functional T cells to overcome T cell exhaustion. When immunotherapies fail, however, it is frequently because the T cell population was already totally exhausted (or became so). Amazingly, it is poorly understood what molecules cause T cells to exhaust themselves as they continuously encounter cancer cells. Understanding how the PKCs control T cell exhaustion is at the very core of every T cell immunotherapy. Discovering the networks of proteins each PKC controls will provide new targets for potential drugs to combine with existing T cell immunotherapies, hopefully leading to improved efficacy for more patients. Projects and Grants Resetting the clock on T cell exhaustion: Targeting protein kinase C to synergize with immune checkpoint blockade Salk Institute for Biological Studies | All Cancers | 2023 Antitumor Immunity in Exceptional Responders to Immune Checkpoint Blockade Salk Institute for Biological Studies | All Cancers, Lung Cancer | 2020 Elucidating cellular and genetic factors associated with tumor resistance to immunotherapies Salk Institute for Biological Studies | All Cancers | 2017 Enhancing immunotherapy-based cancer treatments through CD40-dependent immunomodulation of the tumor microenvironment Yale University | Lung Cancer, Melanoma | 2014
