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A Novel Regulator of Antitumor Immunity and Immunotherapy

Award Number: R01CA288321
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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A Novel Regulator of Antitumor Immunity and Immunotherapy - ABSTRACT Tumor antigen-triggered T cell receptor (TCR) signaling in the cytoplasm and transcriptional/epigenetic control in the nucleus are central to CD8+ T cell-dependent antitumor immunity. However, strong and persistent antigen stimulation leads to immune exhaustion. Compared to tumor drainage lymph nodes, the tumor microenvironment (TME) contains higher amounts of tumor antigens and their prolonged presentation to tumor- infiltrating CD8+ T cells can exacerbate T cell exhaustion and immune evasion. Except for co-inhibitory receptors, it is largely unknown how T cells adapt to the antigen-rich milieu of TME. Better understanding of the mechanisms underlying TME-unique regulation of T cell functions could inform novel therapies aimed at reinvigorating the antitumor potential of exhausted CD8+ T cells. The overarching scientific objective of our proposed work is to determine how negative elongation factor (NELF), known for its function in RNA polymerase II (Pol II) pausing, regulates CD8+ T cell activities in a TME- unique manner. Our preliminary work suggests that NELF is both necessary and rate-limiting in promoting the antitumor activity of CD8+ T cells. Of note, this NELF function is unique to CD8+ T cells within the TME, but not in tumor drainage lymph nodes. Furthermore, our published and unpublished data point to potential dual actions of distinct subcellular pools of NELF: while nuclear NELF participates in transcriptional and epigenetic programs, cytoplasmic NELF attenuates TCR signaling. We hypothesize that the combined actions of NELF likely contribute to stronger T cell memory and less T cell exhaustion. Built upon rigorous scientific premises and multidisciplinary expertise, we will validate this novel hypothesis by deciphering the TME-unique function of NELF (Aim 1), interrogating its dual molecular actions in the nucleus and cytoplasm (Aim 2), and exploring the utility of NELF overexpression in boosting efficacy of anticancer immunotherapies (Aim 3). The concept that NELF has a TME-unique function in antitumor immunity is novel. Furthermore, the proposed dual actions of NELF clearly deviate from the Pol II pausing-exclusive paradigm of NELF biology. The proposed work in this multi-PI R01 proposal promises to shed light on a previously unappreciated regulator of TME-unique functions of tumor-infiltrating T cells, with potential for a sustained impact on the understanding of antitumor immunity. From a translational perspective, discoveries from this project could inform more effective approaches to boost T cell memory and overcome T cell exhaustion, thus helping address a significant barrier and unmet clinical need in anticancer immunotherapies.


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 = $656,704 )
2026	2026	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	3	2/27/2026	NON-COMPETING CONTINUATION	$656,704
														Subtotal = $656,704

Issue Date FY: 2025 ( Subtotal = $656,704 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$65,671
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	2	2/17/2025	NON-COMPETING CONTINUATION	$591,033
														Subtotal = $656,704

Issue Date FY: 2024 ( Subtotal = $669,506 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cancer Biology Research	000	1	3/14/2024	NEW	$669,506
														Subtotal = $669,506

Grand Total All Awards = $1,982,914

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A Novel Regulator of Antitumor Immunity and Immunotherapy

Award Number: R01CA288321

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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