Programming of Checkpoint Blockade Responsive Stem-like T cells in Chronic Viral Infections and CAR T Cell Immunotherapy of Solid Tumors 4757

Abstract Description Stem-like progenitor exhausted T cells (TPEx) are critical for maintaining long-term resistance against chronic viral infections and cancer, and represent an important target for functional reinvigoration for PD-1 checkpoint blockade immunotherapy (CBI). Mechanisms involved in the programming of TPEx cells during priming, remain to be clearly defined. Here we show a crucial fate-deterministic role of tempered IL-2 signals in programming TCF-1Hi stem-like precursors (TPEX) during the initial priming of T cell responses, which are durable and respond to anti-PD-1 therapy in later stages of exhaustion. In the context of human tumors, scRNA-seq analyses of antigen-specific tumor infiltrating lymphocytes from melanoma, head and neck cancer and lung cancer patients show an inverse relationship of IL-2 signaling signature with stemness of exhausted T cells, as well as checkpoint blockade therapy outcomes. Notably, regulated IL-2 signals during CAR-T cell product manufacturing also promoted the development of long-lived, stem-like TCF-1Hi cells, capable of synergy with PD-1 CBI for enhanced tumor control. Thus contrasting the well-established role of strong IL-2 signals through IL-2Ra in vigorous effector CTL differentiation during PD-1 CBI at later stages of chronic disease, these studies highlight a distinctive role of tempered IL-2 signaling through the IL-2Rb/g heterodimer in programming the long-lived, PD-1 therapy responsive stem-like T cells during the initial priming phase. Funding Sources National Institutes of Health (AI132819 to SS and AI103748 to SS; AI154363 to VK) Topic Categories Cytokines and Chemokines and Their Receptors (CCR)