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Discovering T cell proteome turnover dynamics to overcome the solid tumor microenvironment

Award Number: DP5OD031863
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Discovering T cell proteome turnover dynamics to overcome the solid tumor microenvironment - PROJECT SUMMARY Cellular therapies are a cornerstone in the field of cancer immunotherapy, and many consider them the next frontier in cancer treatment. Despite the success of adoptive cell therapies for the treatment of hematologic cancers, the question of its effective use against solid tumors remains unresolved. The extremely complex biology of solid tumors driven by tumor heterogeneity amongst and within patients is largely the source of failure. New approaches are needed to inform the engineering adoptive T cells and to monitor a patient’s T cell capacity to circumvent the multitude of barriers present in solid tumors. The ability of a cell to dynamically adjust proteome composition is essential during stress. For that reason, protein turnover rates are optimized to balance energy- saving stability and dynamic flexibility serving as a rapid mechanism for activation or inhibition of signaling pathways when cells respond to environmental changes. While it is common to ask the question “how do T cells respond to stress?” we intend to shift the paradigm to asking a fundamentally different question “how are T cells prepared for encountering stress?” The precise set of proteins T cells depend on to ensure adequate plasticity remains elusive. We have conceived and developed a novel integrative multi-omic technique for the analysis of proteome turnover dynamics. This technique integrates proteome, transcriptome, and protein dynamic profiling approaches for the identification of protein “operating points”, a measure of protein dynamic nature. We hypothesize that the ability of a T cell to adapt, through dynamic proteome control, determines persistence and function in solid tumors. Unveiling mechanisms that endow T cells with superior adaptability and the capacity to overcome solid tumors will be of great clinical interest in cellular therapy development. Further, identifying new ways to determine T cell fitness in immune monitoring will not only have implications in the treatment of cancer but, many other immune driven conditions as well. The aims of the study are 1) Define proteome turnover changes in response to co-stimulation and exhaustion, 2) Manipulate protein turnover rates to enhance T cell persistence, and 3) Utilize protein turnover rate measurements in patient immune monitoring.


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: 2024 ( Subtotal = $374,355 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Trans-NIH Research Support	000	4	8/16/2024	NON-COMPETING CONTINUATION	$374,355
														Subtotal = $374,355

Issue Date FY: 2023 ( Subtotal = $374,519 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Trans-NIH Research Support	000	3	8/31/2023	NON-COMPETING CONTINUATION	$374,519
														Subtotal = $374,519

Issue Date FY: 2022 ( Subtotal = $380,000 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Trans-NIH Research Support	000	2	8/25/2022	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $380,000

Issue Date FY: 2021 ( Subtotal = $380,000 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Trans-NIH Research Support	000	1	9/14/2021	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $1,508,874

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Discovering T cell proteome turnover dynamics to overcome the solid tumor microenvironment

Award Number: DP5OD031863

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/14/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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