Project Grant R01CA290743

SUSTAINING ANTITUMOR EFFECTOR CD8+ T CELLS FOR CANCER THERAPY - ANTITUMOR RESPONSES OF CD8+ T CELLS ARE TIGHTLY REGULATED BY DISTINCT METABOLIC FITNESS. IT HAS BEEN REPORTED THAT TERMINALLY DIFFERENTIATED EXHAUSTED T CELLS DISPLAY IMPAIRED MITOCHONDRIAL RESPIRATION AND/OR GLYCOLYSIS AND SUCH LIMITED METABOLIC RESERVE REINFORCES T CELL DYSFUNCTIONALITY ESPECIALLY IN THE TUMOR MICROENVIRONMENT OF ADVANCED CANCER. THE MOLECULAR MECHANISM BY WHICH SUSTAINING METABOLIC FITNESS IN HIGHLY DIFFERENTIATED EFFECTOR T CELLS (TEFF) FOR ENHANCEMENT OF ANTI- TUMOR IMMUNITY HAS BEEN ILL-DEFINED. INTERESTINGLY, INCREASED LEVELS OF GLUTATHIONE (GSH) ARE OBSERVED IN THE MAJORITY OF TUMORS SUCH AS BREAST CANCER AND MELANOMA CONTRIBUTING TO CANCER PROGRESSION AND TREATMENT RESISTANCE IN PART BY PREVENTING GLUTATHIONE PEROXIDASE 4 (GPX4) DEPENDENT FERROPTOSIS, AN IRON-DEPENDENT PROGRAMMED CELL DEATH. HOWEVER, THE ROLE OF THE GSH- GPX4 METABOLIC AXIS IN MODULATING THE ANTITUMOR RESPONSE OF CD8+ T CELLS REMAINS ELUSIVE. BASED ON THE PRELIMINARY RESULTS WE OBTAINED, THE CENTRAL HYPOTHESIS IS THAT SUSTAINING THE GSH-GPX4 AXIS WHILE INACTIVATION OF ADENOSINE A2A RECEPTOR (A2AR) IS CRITICAL FOR THE GENERATION OF LONG-LIVED TEFF FOR DURABLE METABOLIC RESPONSES AGAINST TUMOR CELLS, AND BIOENGINEERING TEFF TO CONDITIONALLY EXPRESS GCLC/GPX4 WITH A2AR INHIBITION IMPROVES IN VIVO PERSISTENCE AND FUNCTION TO PROLONG THE EFFICACY OF ADOPTIVE CELL THERAPY (ACT). TO TEST THIS HYPOTHESIS, WE WILL DEFINE THE DOWNSTREAM METABOLIC AND CELLULAR EFFECTS OF SUSTAINING THE GSH-GPX4 AXIS WHILE INACTIVATION OF A2AR SIGNALING IN TEFF CELLS, AND FURTHER DETERMINE THE SAFETY AND EFFICACY OF ADOPTIVE THERAPY OF MURINE AND HUMAN T CELLS BIOENGINEERED TO EXPRESS GCLC/GPX4 WITH A2AR INHIBITION.