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Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors

Award Number: F31CA232380
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors - Project Summary/Abstract: CD8+ T cells differentiate into cytotoxic T lymphocytes (CTLs), to directly engage malignant cells and cause their lysis via exocytosis of cytotoxic granules. However, the regulation underlying these responses to tumors is ill- defined and generally unsuccessful compared responses to acute viral infections. In addition, studies have shown that while inhibitory signal blockade can restore some T cell function, it does not lead to global epigenetic reprogramming of dysfunctional cells. Nevertheless, basic studies to clarify the factors and mechanisms that control chromatin structure and transcription in CD8 T cells reacting to tumors and viral infection are likely to identify how this can be achieved. To address these issues, I am interested in defining how transcription factor Runx3 and chromatin regulator Mll1 work separately and together to effect genome wide transcript expression, chromatin accessibility, and inhibitory receptor expression in CTLs infiltrating triple negative breast cancers. I provide evidence that both Runx3 and Mll1 expression levels can manipulate PD-1 expression and that Mll1 expression is linked to Runx3. I hypothesize that by studying how these two genes work independently and in a coordinated fashion I can define a network of gene regulation and chromatin accessibility that programs PD-1 expression, and more broadly, understand more about the genetic architecture of CTLs infiltrating non-lymphoid tissues. To do, I propose two specific aims: Elucidate how Runx3 programs CD8+ T cell differentiation during anti-tumor responses & Understand the role of Mll1 in determining CTL function in tumor microenvironments. Both aims will utilize a model of murine triple negative breast cancer, E0771, tagged with lymphocytic choriomeningitis virus antigen GP33 to allow for antigen specific tumor targeting in proposed experiments. In Aim 1, I will identify the key genetic and epigenetic landscapes through which Runx3 acts and how this relates to PD-1 function. Previous research has shown that Runx3 is necessary to generate non-lymphoid and tumor residency and also programs the expression of inhibitory genes such as PD-1. By studying these features, I can identify what pathways this apical transcription factor works through and how this effects PD-1 expression. In Aim 2, I will be investigating the role Mll1 plays in similar pathways. Mll1 was identified through an in vitro RNAi screen for chromatin regulators that modulated co-inhibitory genes. From this screen Mll1, and genes that make up the MLL1/2 complex, are heavily implicated in inhibiting PD-1 expression. By looking at how Mll1 functions in CTLs within the TME and what changes it promotes both in accessibility and methylation, I can understand how these changes in chromatin directs CTL fates in tumors. Combined with understanding Runx3 and the relationship between the genes, this will provide detailed evidence into the fundamental genetic architecture underlying CTLs accumulation and maintenance within tumors.


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: 2023 ( Subtotal = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	002	2	1/19/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	001	2	1/19/2023	NON-COMPETING CONTINUATION	$0
2023	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	000	1	1/19/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $5,856 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	002	2	9/7/2021	SUPPLEMENT FOR EXPANSION	$5,856
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	000	2	8/26/2021	NON-COMPETING CONTINUATION	$0
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	001	2	9/7/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $5,856

Issue Date FY: 2020 ( Subtotal = $32,520 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	000	2	3/20/2020	NON-COMPETING CONTINUATION	$32,520
														Subtotal = $32,520

Issue Date FY: 2019 ( Subtotal = $32,016 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	000	1	3/28/2019	NEW	$32,016
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Cancer Research Manpower	001	1	3/28/2019	NEW	$0
														Subtotal = $32,016

Grand Total All Awards = $70,392

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Dissecting the roles of Runx3 and Mll1 in dysfunctional T cell responses to tumors

Award Number: F31CA232380

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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