Acetylation modulates T cell receptor signaling

About This Grant

PROJECT SUMMARY Title: Acetylation modulates T cell receptor signaling PA-25-301 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) Suboptimal TCR signaling is one of the major immune resistance mechanisms hampering the efficacy of cancer immunotherapy. Accordingly, restoration of optimal TCR signaling is of crucial importance to overcome immunologic barriers within the tumor microenvironment. We have recently identified a previously unrecognized role for acetylation as an important post-translational process that regulates TCR signaling. Our preliminary data demonstrate that Sirt2-/- mice mount superior anti-tumor immune responses in vivo and in vitro. Strikingly, we have observed amplified calcium flux and TCR signaling in Sirt2-/- T cells. Further mechanistic studies revealed that increased acetylation of Lck, drove enhanced T cell activation and effector functions to overcome T cell exhaustion. Based on these preliminary data, we will test the central hypothesis that acetylation of Lck by Sirt2 abrogation during cellular immunotherapy endows resistance to T cell exhaustion by amplified proximal TCR signaling within the TME. In Aim 1, we will define the role of acetylation in Lck activity and proximal TCR signaling. In Aim 2, we will dissect the intersection between acetylation and other known mechanisms regulating Lck in the context of T cell exhaustion. In Aim 3, we will optimize Sirt2 abrogation in melanoma and NSCLC TIL therapy and TCR-T therapy. These studies will establish acetylation as a new post-translational mechanism modulating TCR signaling and validate Sirt2 as an actionable target to overcome T cell exhaustion distinct from existing immune checkpoint pathways. Ultimately, we propose to improve the efficacy of T cell therapeutics via genetic manipulation of Sirt2 thus opening new frontiers for combinatorial immunotherapeutic strategies. Justification for Use of Vertebrate Animals: Our studies are focused on the role of Sirt2 in TCR signaling and effector functions. The immune system is complex and studies involving interactions between distinct cell types of the immune system can only be performed with appropriate animal models. Because we will evaluate the impact of Sirt2 on cancer, animal models that appropriately model the human disease are required. An in vivo model is an established procedure that provides valuable biological information for the potential of cancer therapy. As a major focus of this proposal is to translate findings to the clinic, in vitro models alone are inadequate. No in vitro or theoretical approaches can mimic the complex cellular interactions that drive immune-mediated responses. The easy handling of mice compared with other types of animals will allow for thorough experiments to fulfill statistical considerations. The results from our proposed studies may identify Sirt2 as appropriate targets for cancer immunotherapy to restore T cell responsiveness to suboptimal tumor antigen presentation.