Project Grant F30CA298502

EVALUATING THE ROLE OF T CELLS IN NF1-PERIPHERAL NERVE SHEATH TUMOR (PNST) PROGRESSION - PROJECT SUMMARY/ABSTRACT NEUROFIBROMATOSIS TYPE 1 (NF1) IS A CANCER PREDISPOSITION SYNDROME CAUSED BY A MUTATION IN THE NF1 TUMOR SUPPRESSOR GENE THAT OCCURS IN 1:3000 LIVE BIRTHS. LOSS OF NEUROFIBROMIN, A GTPASE ACTIVATING PROTEIN FOR P21 RAS, CAUSES HYPERACTIVATION OF THE RAS PATHWAY THAT LEADS TO THE FORMATION OF PLEXIFORM NEUROFIBROMAS (PNF) IN UP TO 50% OF INDIVIDUALS WITH NF1. IN THE MAJORITY OF NF1 PATIENTS, PNF GROW SLOWLY, TYPICALLY REACHING STABILITY IN ADULTHOOD. HOWEVER, A SUBPOPULATION OF NF1 PATIENTS EXPERIENCE PROGRESSION TO ATYPICAL NEUROFIBROMATOUS NEOPLASM OF UNCERTAIN BIOLOGIC POTENTIAL (ANNUBP) AND TRANSFORM TO MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (MPNST). MPNSTS ARE THE LEADING CAUSE OF PREMATURE DEATH IN NF1 PATIENTS WITH A 5-YEAR SURVIVAL RATE OF 20- 50%. THEREFORE, UNDERSTANDING THE MOLECULAR AND CELLULAR INTERACTIONS THAT MEDIATE PROGRESSION ALONG THE PERIPHERAL NERVE SHEATH TUMOR (PNST) CONTINUUM IS CRITICAL TO IMPROVING NF1 PATIENT SURVIVAL. THE GENETIC EVENTS GOVERNING NEUROFIBROMA PROGRESSION AND MALIGNANT TRANSFORMATION HAVE BEEN EXTENSIVELY STUDIED AND SEVERAL KEY DRIVER EVENTS HAVE BEEN IMPLICATED. HOWEVER, PRECLINICAL AND NATURAL HISTORY STUDIES SUGGEST THAT THESE GENETIC CHANGES MAY NOT FULLY ACCOUNT FOR THE CLINICAL HETEROGENEITY OF PNF AND ANNUBP PRECURSOR LESIONS AND THEIR EVOLUTION TO MPNST. THEREFORE, I POSTULATE THAT ADDITIONAL FACTORS EITHER INTRINSIC TO NEOPLASTIC SCHWANN CELL PROGENITORS OR WITHIN THE TUMOR MICROENVIRONMENT PLAY A CRITICAL ROLE IN MODULATING THE GROWTH AND MALIGNANT POTENTIAL OF NEUROFIBROMA. MY RECENT WORK DEFINING THE SPATIAL GENE EXPRESSION PROFILE OF HUMAN NF1-ASSOCIATED TUMORS IDENTIFIED ALTERATIONS IN SIGNATURES OF IMMUNE SURVEILLANCE, INCLUDING T CELL ACTIVATION AND CYTOTOXICITY, ACROSS THE PNST CONTINUUM. ANTI-TUMOR T CELL RESPONSE SIGNATURES WERE UPREGULATED IN ANNUBP, WHEREAS PRECURSOR LESIONS THAT PROGRESSED TO MPNST WERE CHARACTERIZED BY SIGNATURES OF T CELL EXHAUSTION. FURTHERMORE, IMMUNOFLUORESCENCE STAINING SHOWED THAT HUMAN ANNUBPS WERE CHARACTERIZED BY INCREASED INFILTRATION OF CD4+FOXP3- AND CD8+FOXP3- T CELLS, WHILE FOXP3+ T CELLS (T REGULATORY CELLS) PREDOMINATED IN MPNST. WHILE THE DENSITY AND FUNCTIONAL STATES OF T CELLS INFILTRATING THE TUMOR MICROENVIRONMENT ARE IMPORTANT PREDICTORS OF THERAPEUTIC RESPONSE AND PROGNOSIS IN MANY HUMAN CANCERS, THE FUNCTIONAL ROLE OF DISTINCT T CELL SUBSETS IN GOVERNING NEUROFIBROMA PROGRESSION TO MPNST REMAINS UNDEFINED. THE OBJECTIVE OF THIS WORK IS TO DEFINE THE T CELL SUBSETS PRESENT AT VARIOUS STAGES OF THE PNST CONTINUUM AND INVESTIGATE THEIR FUNCTIONAL ROLE IN TUMOR PROGRESSION. I HYPOTHESIZE THAT EFFECTOR CD4 AND/OR CYTOTOXIC CD8+ T CELLS ARE CRITICAL IN PREVENTING MALIGNANT TRANSFORMATION OF PNF AND ANNUBP PRECURSORS. ULTIMATELY, THESE STUDIES WILL ADVANCE OUR UNDERSTANDING OF THE FUNCTIONAL ROLE OF T CELL SUBSETS ACROSS THE PNST CONTINUUM AND INFORM FUTURE DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR PATIENTS WITH NF1.