# Breaking down tumor immune privilege through targeted hypoxia reduction

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $481,691

## Abstract

PROJECT SUMMARY/ABSTRACT
Tumor hypoxia predicts poor outcomes across all cancers and is a well-established source of resistance to both
chemo- and radiotherapy. We have shown that T cells fail to thrive in hypoxic zones of cancer underlying the
failure of checkpoint blockade for immune “cold” indications such as pancreatic and prostate cancer. While our
prior work relied on our serendipitous discovery that the hypoxia-activated prodrug, TH-302, could efficiently
reduce tumor hypoxia, there have been no studies to identify the most effective means to reduce hypoxia in
cancer. Mechanistically, tumor hypoxia results from the combination of diminished oxygen supply coupled with
enhanced tumor oxygen consumption. While each of these influences helps to foster hypoxia and nucleate an
immune suppressive state, nothing is known of their relative importance in establishment of the hypoxic state
itself, nor of their differential impact on tumor-infiltrating T cells within hypoxic regions. Further, we lack an
understanding of the factors governing durability of hypoxia-reduction, and of any interventions to limit tumors’
capacity to restore the hypoxic state. At a deeper level, the precise molecular signals triggered by hypoxia, which
reprogram myeloid and myofibroblast cells in the stroma to adapt metabolically to the hypoxic state and acquire
immune suppressive function also remain unclear. We therefore hypothesize that tumor hypoxia and
associated immune suppressive programming of the myeloid and myofibroblast stroma can be reduced
through both local tissue remodeling and through limitation of tumor oxygen metabolism. Our first aim is
to determine the kinetics of hypoxia and immune infiltrate modulation by hypoxia-activated prodrugs, oxidative
phosphorylation (OxPhos) inhibitors, and anti-angiogenic agents. For each class, we will establish the kinetics
by which they reduce hypoxia, how durable that reduction is post-therapy, and whether re-treatment can
eliminate re-emergent hypoxia. This first of its kind systematic study will not only reveal optimal approaches for
reducing tumor hypoxia in an immune-potentiating context but will also provide insights into the relative
contribution of disrupted oxygen supply versus elevated tumor oxygen consumption toward establishing hypoxia.
Second, we will investigate the impact of OxPhos inhibitors on both tumor and T cell metabolism and hypoxic
fitness. We will assess how three inhibitors of OxPhos metabolism, which target distinct subunits of Complex I,
impact tumor versus T cell metabolism, function, and hypoxic adaptation. These studies will provide critical
insight into whether tumor oxygen consumption can be inhibited in a manner which compromises tumor hypoxic
fitness and immune privilege without damaging the functional capacity of anti-tumor immunity. The third aim of
this proposal utilizes mice lacking hypoxia-inducible factor 1-alpha (HIF1α) or HIF2α in either their tumor myeloid
stroma or myofibroblasts ...

## Key facts

- **NIH application ID:** 10028301
- **Project number:** 1R01CA251816-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael A. Curran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,691
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028301

## Citation

> US National Institutes of Health, RePORTER application 10028301, Breaking down tumor immune privilege through targeted hypoxia reduction (1R01CA251816-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10028301. Licensed CC0.

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