# Characterizing and Targeting the Hypoxic T Cell Surfaceome to Promote Immune Function in Cancer

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $65,994

## Abstract

Project Summary
Recent efforts have focused on developing T cell-based immune therapies to treat cancer. However, these
therapies have several limitations, including minimal efficacy against solid tumors. One characteristic of the
solid tumor microenvironment is low oxygen availability, or hypoxia. It is generally thought that tumor hypoxia
suppresses the anti-tumor immune response. The goal of this project is to improve our understanding of how T
cells respond to hypoxia and reveal new strategies for increasing the anti-tumor function of hypoxic T cells.
These findings will ultimately inform the engineering of T cell therapies to overcome the hypoxic tumor
microenvironment. Two key T cell subtypes that modulate anti-tumor immune function are pro-inflammatory T
effector (Teff) and anti-inflammatory T regulatory (Treg) cells. Previous studies examining the effects of
hypoxia on these cell types are highly discordant. Clarifying the effects of hypoxia on Teff and Treg function will
expand our understanding of basic T cell biology and potentially identify new means of enhancing anti-tumor T
cell activity in hypoxia. Here, we hypothesize that hypoxia alters T cell surface proteins (the “surfaceome”) and
T cell function in a manner consistent with a net immunosuppressive effect. To test this hypothesis, we will
utilize a combination of studies with primary human T cells, animal models, and patient samples. We will
employ our established surfaceomic and phage display-based recombinant antibody engineering strategies to
examine the effect of hypoxia on suspected hypoxia-induced antigens (HIAs) as well as to identify novel HIAs.
We will first apply these techniques to isolated primary human Teff and Treg cells cultured in normoxic or
hypoxic conditions in vitro. We will then examine hypoxic tumor-infiltrating T cells derived from humanized
mouse models of pancreatic cancer as well as patient pancreatic tumor samples. This surfaceomic profiling,
combined with T cell proliferation, activation, and migration studies, will provide a comprehensive picture of
hypoxia-induced T cell surface protein and functional changes. Furthermore, we will engineer novel inhibitory
antibodies or bispecific constructs targeting both suspected and newly-identified HIAs. These engineered
proteins will be tested for Teff/Treg modulatory function in hypoxic culture and in a humanized pancreatic
cancer mouse model with the ultimate goal of identifying strategies to promote hypoxic Teff function and
immune-mediated tumor killing. In the long term, the basic biological insights and antibody tools gained from
the proposed studies will inform ongoing efforts to treat cancer using T cells and will lay the foundation for
future therapeutics to boost immune targeting of hypoxic tumors.

## Key facts

- **NIH application ID:** 10149260
- **Project number:** 5F32CA239417-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** James Robert Byrnes
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149260

## Citation

> US National Institutes of Health, RePORTER application 10149260, Characterizing and Targeting the Hypoxic T Cell Surfaceome to Promote Immune Function in Cancer (5F32CA239417-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149260. Licensed CC0.

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