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Elucidating The Roles of PIK3IP1/TrIP Regulation on Distinct T Cell Subsets in the Context of Cancer

Award Number: F31CA261039
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 05/30/2024

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Elucidating The Roles of PIK3IP1/TrIP Regulation on Distinct T Cell Subsets in the Context of Cancer - PROJECT SUMMARY The signaling pathways involving phosphoinositide-3-kinases (PI3Ks) are highly conserved and tightly regulated to influence the activation, proliferation, and survival of all cell types. PI3K signaling plays a major role in T cell responses to antigen due to its position directly downstream of T cell receptor (TCR)/CD28 ligation. Our lab has recently shown that the cell surface protein TrIP (Transmembrane Inhibitor of PI3K, gene name: Pik3ip1) has a distinctly high expression on T cells and is capable of downregulating PI3K signaling in CD4+ T cells, acting as a negative regulator of T cell immune responses. These studies revealed that CD4+ T cells lacking TrIP expression exhibit a more Th1 inflammatory phenotype compared to WT controls both in vivo and in vitro. These data have led us to propose that TrIP restricts the inflammatory activity of CD8+ T cells, and that targeting/knockout of this negative regulator may promote anti-tumor immunity. I have already obtained preliminary data demonstrating that CD8+ T cell-specific TrIP knockout mice (TrIPfl/flE8icre) are resistant to growth of syngeneic tumors. In addition to increased tumor resistance, we have also found that tumors harvested from our TrIPfl/flE8icre knockout mice contain twice as many infiltrating T cells compared to their WT counterparts. We also found that CD8+ T cells were the main drivers of this increased T cell infiltration, as their frequency was double that of the CD4+ population. These preliminary data are the basis of our proposal aimed at further elucidating cell-intrinsic effects of TrIP activity in CD8+ T cells, including its impact on antitumor immunity. These studies will not only improve our understanding of TrIP as a negative immune regulator, but also inform on the potential for TrIP as a future immunotherapeutic target.


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: 2025 ( Subtotal = -$33,146 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	3	3/25/2025	NON-COMPETING CONTINUATION	-$22,626
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	2	3/25/2025	NON-COMPETING CONTINUATION	-$10,520
														Subtotal = -$33,146

Issue Date FY: 2024 ( Subtotal = $22,626 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	3	1/29/2024	NON-COMPETING CONTINUATION	$42,537
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	002	3	7/3/2024	NON-COMPETING CONTINUATION	-$21,191
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	3	5/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $22,626

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	2	1/30/2023	NON-COMPETING CONTINUATION	$46,752
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	2	6/14/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	001	1	1/5/2022	NEW	$0
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	000	1	1/5/2022	NEW	$46,036
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Research Manpower	002	1	8/12/2022	NEW	$716
														Subtotal = $46,752

Grand Total All Awards = $83,926

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Elucidating The Roles of PIK3IP1/TrIP Regulation on Distinct T Cell Subsets in the Context of Cancer

Award Number: F31CA261039

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 05/30/2024

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