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Reprogramming tumor-reactive CD8 T cells by targeting the IL-21-BATF pathway to treat melanoma

Award Number: F30CA246920
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Reprogramming tumor-reactive CD8 T cells by targeting the IL-21-BATF pathway to treat melanoma - Project Summary Advanced melanoma is a major target of cancer immunotherapy research due to its poor survival rate even with recent treatment advances. Current strategies focus on CD8 T cells which enter a dysfunctional state in the tumor microenvironment. Recent studies have found that intratumoral CD8 T cells consist of a heterogeneous population of memory-like progenitor, effector and terminally exhausted cells that exhibit differing functional and self-renewal capacities. However, the cellular and molecular processes involved in the differentiation of these subsets within melanoma is not well understood. Exploring the intricacies of CD8 T cell differentiation towards an effector profile can identify novel immunotherapeutic targets. Thus, the long-term goal of this project is to elucidate the mechanisms regulating effector CD8 T cell differentiation and function in melanoma. CD4 T cell production of cytokines provide help to CD8 T cells. Recent studies have uncovered the cytokine IL- 21 as a critical signal produced by CD4 T cells to help promote CD8 T cell maintenance in chronic infection. However, the direct effects of IL-21 produced by CD4 T cells on CD8 T cell differentiation and function in cancer remains unknown. Preliminary data presented in this proposal suggest that IL-21 producing CD4 T cells induce an effective antitumor response dependent on CD8 T cells. Additionally, it has been previously found that IL-21 signaling induces the transcription factor BATF, which is known to cooperatively bind with IRF4 to induce changes in the chromatin landscape. This has led to the hypothesis that the IL-21-BATF pathway enhances melanoma-infiltrating effector CX3CR1+ CD8 T cells and their function via BATF-IRF4 mediated transcriptional regulation. Aim 1 will determine if adoptively transferred IL-21-producing CD4 T cells enhance effector CX3CR1+ CD8 T cell differentiation. The effect of CD4 T cell-derived IL-21 on CD8 T cell differentiation and function will be determined in vivo. Then, it will be determined if IL-21R signaling is intrinsically necessary for the CD8 T cell response to IL-21 producing CD4 T cell help. Aim 2 will investigate the mechanism of BATF-mediated tumor-infiltrating CD8 T cell differentiation. These experiments will determine if BATF-IRF4 interaction is necessary to promote tumor-infiltrating CX3CR1+ CD8 T cells. Furthermore, changes in BATF-mediated chromatin accessibility in CD8 T cell differentiation and function will be assessed. This proposal will help in understanding how CD8 T cells differentiate and function in melanoma. This is in line with the mission of NCI, as the results of this project could lead to the identification of BATF as a novel therapeutic mechanism to enhance effector CD8 T cell differentiation to fight cancer.


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 = -$224 )
2025	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	000	4	10/23/2024	NON-COMPETING CONTINUATION	-$224
														Subtotal = -$224

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	001	4	5/22/2023	NON-COMPETING CONTINUATION	$942
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	000	4	1/5/2023	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	001	3	6/9/2022	NON-COMPETING CONTINUATION	$716
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	000	3	2/1/2022	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $48,126 )
2021	2021	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	000	2	12/8/2020	NON-COMPETING CONTINUATION	$47,610
2021	2021	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	001	2	2/1/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $48,126

Issue Date FY: 2020 ( Subtotal = $47,610 )
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	002	1	2/11/2020	NEW	$504
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	001	1	12/19/2019	NEW	$0
2020	2020	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Research Manpower	000	1	12/19/2019	NEW	$47,106
														Subtotal = $47,610

Grand Total All Awards = $199,958

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Reprogramming tumor-reactive CD8 T cells by targeting the IL-21-BATF pathway to treat melanoma

Award Number: F30CA246920

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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