# Molecular mechanisms underlying T cell resistance to PD-1 signaling

> **NIH NIH R35** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $422,500

## Abstract

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...

## Key facts

- **NIH application ID:** 10891572
- **Project number:** 5R35GM150989-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anna S Tocheva
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,500
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891572

## Citation

> US National Institutes of Health, RePORTER application 10891572, Molecular mechanisms underlying T cell resistance to PD-1 signaling (5R35GM150989-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891572. Licensed CC0.

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