Investigating the role of protein-acyltransferase zDHHC5 in T cell antitumor immunity

PROJECT SUMMARY/ABSTRACT: Investigating the role of protein-acyltransferase zDHHC5 in T cell antitumor immunity The potential for long-lasting, protective antitumor immunity has become feasible with cutting-edge cancer treatments such as Immune Checkpoint Blockade (ICB), adoptive cell transfer therapies, and cancer vaccines. Despite an increasing number of patients meeting the eligibility criteria for these treatments, a significant portion does not experience any benefits, ushering in the era of combination therapy. Examination of tumor microenvironments through high-throughput sequencing and various in vivo models has uncovered distinct transcriptional states, epigenetic modifications, proteomic variances, and metabolic profiles distinguishing responders from non-responders to immunotherapies. These findings underscore the critical importance of comprehending the molecular mechanisms underlying these observed differences, particularly the circumstances in which interferon-producing and interferon-stimulated antigen-specific cytotoxic T cells prove effective in eliminating tumors. We propose that the protein acyltransferase, zDHHC5, plays a key role in regulating the kinetics of STAT1 signaling, thereby influencing the response of T cells to local interferon signaling. The biochemical examination of palmitoylated STAT1 reveals a dependence on the expression of zDHHC5, with interferon gamma inducing this palmitoylation. Our bioinformatic analysis indicates an upregulation of zDHHC5 in early activated T cells, a finding confirmed by assessing protein levels in activated mouse and human T cells. Furthermore, T cells from melanoma patients treated with anti-PD1 (pembrolizumab) and exhibiting no tumor recurrence display significantly higher zDHHC5 transcripts compared to those from patients experiencing recurrence. In our initial murine tumor model, T cell-conditional zDHHC5 knockout mice demonstrate the essential role of zDHHC5 in T cell-dependent antitumor immunity, as immunogenic MC38 tumors exhibit significantly accelerated growth in these mice. We seek to characterize the molecular mechanism of STAT1 palmitoylation at the subcellular, cellular, and organismal levels. Furthermore, we plan to test the translational impact of zDHHC5 by modulating its expression in preclinical murine models of immunotherapy.