PROJECT SUMMARY/ABSTRACT Despite modern combination therapies, patients with peripheral T-cell lymphoma (PTCL) continue to experience high rates of refractory disease and early relapse. The PDCD1 gene, which encodes the programmed cell death protein 1 (PD-1) immune checkpoint receptor, is a key tumor suppressor in T-cells and is inactivated in the malignant cells of 20%–30% of patients across most aggressive PTCL subtypes. The highest frequencies of PDCD1 deletions have been detected in patients with advanced disease stages and are associated with a poor prognosis. Clinical trials have revealed multiple cases of PTCL hyperprogression or de novo development after anti-PD-1 checkpoint inhibitor treatment. Despite this, the molecular and tumor biological mechanism underlying the PD-1 tumor suppression remain unclear. Through the studies that form the basis of this proposal, we discovered that PD-1 tumor suppression is a T-cell-specific biological mechanism to prevent malignant T-cell transformation at three distinct levels: i) PD-1 inhibits oncogene-triggered metabolic reprogramming, ii) PD-1 safeguards against tumorigenic lipid production, and iii) PD-1 suppresses oncogenic transcription factor programs. The proposed studies will establish this previously unrecognized conceptual framework and uncover disease-specific vulnerabilities in cancer cells of patients with PTCLs that can be exploited for therapy. Considering the fundamental role of the PD-1 checkpoint receptor in driving T-cell exhaustion and dysfunction in tumor microenvironments, we predict that our results will have broader implications for T-cell biology. The applicant has a multidisciplinary background in mathematics/computational biology and is an M.D./Ph.D.-trained physician-scientist with extensive research experience in PTCLs. We propose a focused career development plan during which the applicant will be trained in the technical, conceptual, and professional skills required to complete the proposed studies and launch an independent research career. Specifically, we have developed five major training goals for the K99 period: i) utilization of patient-derived PTCL xenografts to dissect PD-1 tumor suppression, ii) metabolic techniques to decipher metabolic flux rates and oncogenic lipid metabolism, iii) a thorough understanding of PD-1 signal transduction and PTCL oncogenes, iv) skills to study oncogenic transcription factor networks, and v) clinical translation. This training will be carried out under the supervision of an outstanding mentoring committee consisting of five world-renowned experts in exactly these domains. The training plan, together with his unique background in computational and molecular biology, clinical medicine, and PTCL research, will place the applicant among a very select group of scientists with the skills and knowledge to effectively pursue interdisciplinary work on the tumor suppressive PD-1 pathway, and will provide the foundation for the applicant to b...