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Breaking down tumor immune privilege through targeted hypoxia reduction

Award Number: R01CA251816
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Breaking down tumor immune privilege through targeted hypoxia reduction - 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 to map the downstream signals responsible for functional and metabolic programming of these cells in response to hypoxia. These studies will provide critical insights allowing clinical hypoxia reduction to improve and with it our capacity for immunotherapy of “cold” cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	11/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $457,607 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	6/14/2024	NON-COMPETING CONTINUATION	$457,607
														Subtotal = $457,607

Issue Date FY: 2023 ( Subtotal = $472,058 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	6/28/2023	NON-COMPETING CONTINUATION	$472,058
														Subtotal = $472,058

Issue Date FY: 2022 ( Subtotal = $472,058 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	7/1/2022	NON-COMPETING CONTINUATION	$472,058
														Subtotal = $472,058

Issue Date FY: 2021 ( Subtotal = $481,691 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	6/28/2021	NON-COMPETING CONTINUATION	$481,691
														Subtotal = $481,691

Issue Date FY: 2020 ( Subtotal = $481,691 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	6/25/2020	NEW	$481,691
														Subtotal = $481,691

Grand Total All Awards = $2,365,105

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Breaking down tumor immune privilege through targeted hypoxia reduction

Award Number: R01CA251816

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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