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 become a successful independent investigator in the field of PTCL
pathobiology and clinical translation.