# Dissecting the role of hypoxia in T cell differentiation in cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $583,740

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunotherapeutic treatments for cancer, especially the use of monoclonal antibody mediated blockade of
`checkpoint' molecules like PD-1, has changed the treatment paradigm for patients with solid tumors like
melanoma. However, only a subset of patients benefit from these therapies, due to several resistance
mechanisms concentrated within the tumor microenvironment (TME), the site of action of cytotoxic T cells. T
cells must contend with physical barriers to infiltration, immunosuppressive cell types, the expression of co-
inhibitory ligands on target cells, and a harsh metabolic environment produced by cancer cells. In addition to T
cell-extrinsic immunosuppression, T cells within tumors have a distinct differentiation trajectory, resulting in
acquisition of an alternative, dysfunctional fate termed exhaustion. Exhausted T cells are terminally
differentiated, hypofunctional upon stimulation, and possess poor capacity to proliferate, a crucial component
of immune memory. We and others have shown that exhausted T cells have severe metabolic deficiencies,
and that metabolic stress within the TME, most notably hypoxia exposure, potentiates differentiation towards
exhaustion. In line with this, we and others have shown that melanoma patients with more oxidative, hypoxic
tumors are more likely to progress on anti-PD1. Thus, the hypoxic TME and the intrinsic functional deficiency
of exhausted T cells are linked. However, how hypoxia and resultant oxidative stress alter T cell differentiation
remain unclear. Our hypothesis is that hypoxia exposure promotes T cell exhaustion, by driving aberrant
chromatin bivalency and loss of transcription, such that hypoxia mitigation treatments will alter T cell
differentiation and support increased T cell function. AIM 1: How does hypoxia drive epigenetic changes that
bias T cell differentiation and function? Hypoxia drives several cellular adaptations, including transcriptional
reprogramming via HIF-1α, induction of reactive oxygen species (ROS), and metabolic shifts. We will A) use in
vitro systems to identify mechanisms of hypoxia contributing to altered histone methylation and bivalency in
murine T cells; and B) determine contributions of hypoxia to the T cell epigenome and explore potential
mitigation strategies in murine tumor models. AIM 2: How do hypoxia reducing regimens alter intratumoral T
cell differentiation in melanoma patients? We and other have shown that targeting tumor cell metabolism or
angiogenesis can increase the oxygen tension within tumors in both mouse models and melanoma patients. In
this Aim, we will take advantage of two investigator-initiated clinical trials in melanoma utilizing metformin or
axitinib in combination with anti-PD-1, and deeply explore transcriptional, epigenetic, metabolic, and functional
outcomes associated with reduction of hypoxia coincident with anti-PD-1. We expect these studies to address
knowledge gaps in the fields of epigenetics, immunolog...

## Key facts

- **NIH application ID:** 10755738
- **Project number:** 5R01CA277473-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Greg M. Delgoffe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $583,740
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755738

## Citation

> US National Institutes of Health, RePORTER application 10755738, Dissecting the role of hypoxia in T cell differentiation in cancer (5R01CA277473-02). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10755738. Licensed CC0.

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