Molecular mechanisms underlying T cell resistance to PD-1 signaling

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ABSTRACT T cell activation initiates a program of differentiation that generates a continuum of different memory T cell states with diverse functional and molecular profiles. Activated T cells upregulate the inhibitory receptor programmed cell death protein 1 (PD-1) to prevent excessive T cell inflammation, autoreactivity and tissue damage. Upon binding to its ligands, PD-1 interferes with the phosphorylation cascade that modulates the quality and quantity of T cell signaling. Cancers evade T cell recognition by engaging PD-1 and consequently PD-1 blocking antibodies restore anti-tumor T cell responses and improve the survival of patients with various malignancies. Unfortunately, the majority of cancer patients do not respond to PD-1 blockade and up to 30% develop inflammatory toxicities highlighting the critical role of PD-1 in the maintenance of immune tolerance. Research into basic PD-1 biology, together with the clinical picture of cancer patients treated with PD-1 blocking antibodies, converge to emphasize that PD-1 engages complex signaling networks to support T cell homeostasis, differentiation and immune responses. Therefore, elucidating the signaling cascades and molecular pathways triggered by PD-1 are paramount to fundamental T cells biology and will lay the foundation for advancing the development of PD-1 targeting therapies. Nevertheless, our knowledge as it pertains to the molecular programs that support PD-1 inhibition in functionally diverse human T cell populations is limited. Furthermore, PD-1 has two ligands with distinct tissues expression patterns and binding affinity, yet the functional consequences of these differences are unknown. Our preliminary data highlight that PD-1 engages unique signaling cascades in ligand specific-manner across the trajectory of naïve to memory differentiation, and that the molecular programs underlying functional, phenotypic and developmental T cell heterogeneity also guide pathways of resistance to PD-1 inhibition. Here we will leverage: (1) quantitative phosphoproteomics to reveal PD-1 ligand specific phosphorylation cascades triggered in functionally distinct T cell populations; (2) functional immuno-assays in combination with scRNA-seq and cellular barcoding to identify transcriptional regulators of PD-1 responsivity across the trajectory of naïve through memory and effector T cell generation; and (3) functional genomics to identify cellular and molecular mediators of resistance to PD-1 inhibition. Successful completion of this proposal will reveal how functional T cell diversity shapes and guides PD-1 triggered cellular and molecular pathways and their associated PD-1 ligand specific dependencies. Collectively, understanding the cellular and molecular etiologies associated with PD-1 responsivity and the mechanisms driving T cell resistance to PD-1 inhibition will further our understanding of the fundamental functions of this critical inhibitory receptor in immunological tolerance and advance novel therapeutic directions targeting PD-1 with implications in cancer, infection and autoimmunity.