REPROGRAMING CAR T CELLS BY TARGETING IKZF-HDAC MEDIATED CHROMATIN REMODELING TO TREAT BREAST CANCER - PROJECT SUMMARY IMMUNOTHERAPIES SUCH CHIMERIC ANTIGEN RECEPTOR T CELL (CART) THERAPY HAVE PROVEN REVOLUTIONARY FOR THE TREATMENT OF CANCER. THESE STRATEGIES FOCUS ON REINVIGORATING CD8 T CELLS THAT ENTERED A DYSFUNCTIONAL STATE TERMED EXHAUSTION WHEN IN THE TUMOR MICROENVIRONMENT. RECENTLY, STUDIES HAVE FOUND THAT THE 'EXHAUSTED' CD8 T CELLS IN CANCER ARE HETEROGENEOUS, CONSISTING OF A SELF-RENEWING PROGENITOR THAT CAN GIVE RISE TO BOTH CYTOLYTIC EFFECTOR CELLS AND NON-CYTOLYTIC EXHAUSTED CELLS. AS SUCH, REDIRECTING THESE PROGENITORS TOWARDS THE EFFECTOR CELLS OFFER A NOVEL THERAPEUTIC APPROACH TO AVOID EXHAUSTION. HOWEVER, THE PROCESSES THAT DRIVE THIS DIFFERENTIATION CHOICE ARE NOT WELL UNDERSTOOD. THEREFORE, THE OVERARCHING GOAL OF THIS FELLOWSHIP IS TO INVESTIGATE THE MECHANISMS REGULATING CD8 T CELL EFFECTOR DIFFERENTIATION AND FUNCTION. UNFORTUNATELY, REINVIGORATION OF CD8 CELLS HAS PROVEN DIFFICULT, AS EXHAUSTION IS EPIGENETICALLY IMPRINTED. WE THUS SCREENED FOR EPIGENETIC REGULATORS AND IDENTIFIED IKAROS ZING FINGER FAMILY OF TRANSCRIPTION FACTORS, WHICH IS KNOWN TO COOPERATIVELY BIND TO HISTONE DEACETYLASE (HDAC) AND SUPPRESS GENE EXPRESSION. STRIKINGLY, OUR PRELIMINARY DATA SHOW THAT IKZF- DEFICIENT CD8 T CELLS GIVE RISE TO A SIGNIFICANTLY HIGHER PROPORTION OF CYTOLYTIC EFFECTOR CELLS DURING VIRAL INFECTIONS. EXCITINGLY, THESE CELLS ALSO UNDERGO ROBUST CELL EXPANSION, RESULTING IN A SEVERAL FOLD CHANGE INCREASE IN TOTAL CELL NUMBERS. HOWEVER, IT REMAINS INCOMPLETELY UNDERSTOOD IF IKZF ABROGATION IS AN EFFECTIVE MODALITY FOR TREATING CANCER AND HOW IKZF FAMILY INDUCES EXHAUSTION. THUS, AIM 1 WILL DETERMINE THE EFFICACY OF IKZF PERTURBATION IN CANCER IMMUNOTHERAPY. AIM 2 WILL THEN DETERMINE THE MOLECULAR MECHANISMS OF IKZF- DEFICIENT DIFFERENTIATION AND EXPANSION. THIS STUDY WILL BE CONDUCTED AT NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE UNDER THE GUIDANCE OF IMMUNOLOGISTS, CANCER BIOLOGISTS, AND MEDICAL ONCOLOGISTS ALLOWING FOR MULTIDISCIPLINARY MENTORSHIP. THESE INSTITUTIONS AND MENTORSHIP WILL PROVIDE EXCELLENT TRAINING IN THE FORM OF RIGOROUS RESEARCH EXPERIENCE, BIOINFORMATIC TRAINING, FOCUSED MANUSCRIPT WRITING, AND PRESENTATIONS AT NATIONAL MEETINGS WITHIN IMMUNOLOGY AND ONCOLOGY. THIS PROJECT WILL LEAD TO A BETTER UNDERSTANDING OF THE MECHANISMS THAT DRIVE CD8 T CELL EXHAUSTION AND POTENTIALLY DISCOVER A NOVEL TREATMENT FOR REDIRECTING CD8 T CELLS TOWARDS ROBUST FUNCTIONALITY, IN LINE WITH THE MISSION OF NCI.