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Myeloid cell-expressed PTPN22 and anti-tumor immunity

Award Number: K00CA274689
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 02/26/2025

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Myeloid cell-expressed PTPN22 and anti-tumor immunity - PROJECT SUMMARY Immunotherapies that block the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 have revolutionized cancer treatment; however, a significant number of patients display resistance to immunotherapy, either de novo or with disease relapse after initial response [1-3]. Immunotherapy-refractory cases have prompted insight into mechanisms of resistance, which should ultimately lead to new strategies to expand clinical efficacy. Primary resistance is linked to lack of immune cell infiltration within the tumor microenvironment (TME), an observation which has prompted deeper investigation into the tumor and host factors that regulate the degree of spontaneous T cell activation and infiltration into tumor sites. One relevant source of inter-patient heterogeneity is the variable presence of polymorphisms (SNPs) in immune-regulatory genes, many of which have been linked previously to the propensity towards autoimmunity. In the F99 phase of this proposed plan, I will evaluate the utility of targeting an autoimmune-associated gene to increase immunotherapy efficacy. A SNP in the tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene is attributed with the greatest risk for autoimmune disease outside mutations in the human leukocyte antigen locus [4-6]. PTPN22 negatively regulates the activation of multiple immune compartments, with loss-of-function variants leading to heightened immune cell activation in mice and humans [7-8]. This increase in immune activity is attributed to the expansion of activated CD8+ T cells, however, work reported to date have utilized global knockout mice (KO), confounding the specific role of PTPN22 in other cell lineages relevant for anti-tumor immunity, in particular myeloid cells. We thus developed a PTPN22fl/fl mouse to study its effect in different immune cell types via conditional KO mouse models. I hypothesize that loss of PTPN22 augments the ability of DCs to activate antigen specific CD8+ T cells through 1) improved priming in the tdLN or recruitment to and/or survival signaling in the TME and that 2) deletion of PTPN22 in macrophages also may potentiate anti-tumor immunity. In the K00 phase of the proposed plan, I aim to identify novel targets governing anti-tumor immunity and immunotherapy efficacy by 1) identifying autoimmune related SNPs whose loss of function variants correlate with increased tumor immune infiltration and 2) characterizing the effect of these targets on tumor progression and immunotherapy response through functional studies using conditional KO mice. This work holds the potential to elucidate novel therapeutic targets to potentiate anti-tumor immunity. My ultimate goal is to become a tenure- track faculty member at a leading academic research institution and conduct NIH funded work contributing to the field of tumor immunology by elucidating anti-tumor immunity and developing novel 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: 2025 ( Subtotal = -$13,552 )
2025	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Research Manpower	001	3	5/19/2025	EXTENSION WITH OR WITHOUT FUNDS	-$13,552
2025	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Research Manpower	000	3	2/13/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = -$13,552

Issue Date FY: 2024 ( Subtotal = $91,204 )
2024	2024	NEW YORK GENOME CENTER, INC.	101 AVENUE OF THE AMERICAS FL 7	NEW YORK	NY	10013	NEW YORK	USA	Cancer Research Manpower	000	3	7/9/2024	EXTENSION WITH OR WITHOUT FUNDS	$91,204
														Subtotal = $91,204

Grand Total All Awards = $77,652

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Myeloid cell-expressed PTPN22 and anti-tumor immunity

Award Number: K00CA274689

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 02/26/2025

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