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Signal transduction and gene induction in lymphocytes

Award Number: R01AI040127
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1991
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Signal transduction and gene induction in lymphocytes - ABSTRACT In the previous project period of this grant, we investigated the transcriptional mechanisms of CD8+ T cell “exhaustion”, a hyporesponsive state observed under conditions of sustained antigen stimulation in cancer and chronic viral infections. Exhausted T cells show decreased proliferation and cytokine production, and upregu- late inhibitory cell surface receptors including CTLA4, PD-1, LAG3 and TIM3. Antibodies to these receptors reverse T cell exhaustion, and their administration to cancer patients forms the basis for “immune checkpoint blockade”, a strategy that has recently been remarkably successful in cancer immunotherapy. Combinations of antibodies to inhibitory receptors show greater efficacy than administration of individual antibodies alone, consistent with the fact that exhausted T cells typically express several inhibitory receptors. Thus understanding the molecular mechanisms that lead to inhibitory receptor expression and T cell “exhaustion/ dysfunction” would complement and enhance the effects of therapies that target combinations of individual inhibitory receptors. We previously showed that the transcriptional programs of anergy and exhaustion are initiated by the transcription factor NFAT, acting in the absence of its partner AP-1 (Fos-Jun). In the course of these studies, we developed an engineered NFAT, CA-RIT-NFAT1, which induces the characteristic features of exhaustion when transduced into CD8+ T cells. To understand the biological implications of this hyporesponsive program, we used mouse models of anti-tumor responses that involving adoptive transfer of tumor-reactive or unreactive TCR- transgenic T cells or T cells bearing chimeric antigen receptors (CAR-T cells). Using these models, we identified Nr4a transcription factors, and other families of transcription factors, as “exhaustion-related” target of NFAT. We further showed that tumor-infiltrating CD8+ T cells lacking all three Nr4a family members displayed a gene expression profile similar to that of activated T cells and rejected tumors more efficiently than control CD8+ T cells. In this application we will test the hypothesis that mouse and human CD4+ and CD8+ tumor-infiltrating T cells (TILs) are functionally silenced by a cell-intrinsic transcriptional program mediated, at least in part, by NFAT and Nr4a transcription factors, and other transcription factors induced by NFAT. In Aim 1, we will define mechanistically the cell-intrinsic roles of Nr4a transcription factors in CD8+ T cell exhaustion. We will ask how Nr4a deletion in TILs overcomes exhaustion, enhances the effector phenotype and promotes tumor regression. In Aim 2, we will examine the roles of other pertinent transcription factors in CD8+ T cell exhaustion, and define the kinetics with which the exhaustion program unfolds. In Aim 3, we will examine the roles of NFAT and Nr4a in primary human T cells bearing exhaustion markers or transduced with CA-RIT-NFAT1, and in TILs isolated from human tumors. Our proposed studies will contribute to a broad mechanistic understanding of the transcriptional mechanisms operating in tumor-infiltrating immune cells, and may spark improved immunotherapies for cancer patients.


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 = $1,976,400 )
2025	2025	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	33	8/7/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,976,400
2025	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	32	8/7/2025	NON-COMPETING CONTINUATION	$0
2025	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	30	12/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,976,400

Issue Date FY: 2024 ( Subtotal = $658,800 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	32	8/15/2024	NON-COMPETING CONTINUATION	$658,800
														Subtotal = $658,800

Issue Date FY: 2023 ( Subtotal = $658,800 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	31	8/3/2023	COMPETING CONTINUATION	$658,800
														Subtotal = $658,800

Issue Date FY: 2022 ( Subtotal = $540,000 )
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	30	8/23/2022	NON-COMPETING CONTINUATION	$540,000
														Subtotal = $540,000

Issue Date FY: 2021 ( Subtotal = $540,000 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	29	7/30/2021	NON-COMPETING CONTINUATION	$540,000
														Subtotal = $540,000

Issue Date FY: 2020 ( Subtotal = $540,000 )
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	28	8/13/2020	NON-COMPETING CONTINUATION	$540,000
														Subtotal = $540,000

Issue Date FY: 2019 ( Subtotal = $540,000 )
2019	2019	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	27	8/12/2019	NON-COMPETING CONTINUATION	$540,000
														Subtotal = $540,000

Issue Date FY: 2018 ( Subtotal = $540,000 )
2018	2018	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	26	9/21/2018	COMPETING CONTINUATION	$540,000
2018	2016	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	25	1/9/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $540,000

Issue Date FY: 2016 ( Subtotal = $435,000 )
2016	2016	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	25	8/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$435,000
														Subtotal = $435,000

Issue Date FY: 2015 ( Subtotal = $435,000 )
2015	2015	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	24	8/12/2015	NON-COMPETING CONTINUATION	$435,000
														Subtotal = $435,000

Issue Date FY: 2014 ( Subtotal = $435,000 )
2014	2014	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	23	8/4/2014	NON-COMPETING CONTINUATION	$435,000
														Subtotal = $435,000

Issue Date FY: 2013 ( Subtotal = $408,900 )
2013	2013	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	22	8/5/2013	NON-COMPETING CONTINUATION	$408,900
														Subtotal = $408,900

Issue Date FY: 2012 ( Subtotal = $435,000 )
2012	2012	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	21	9/24/2012	COMPETING CONTINUATION	$435,000
														Subtotal = $435,000

Issue Date FY: 2010 ( Subtotal = $551,078 )
2010	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	20	6/16/2010	NON-COMPETING CONTINUATION	$551,078
														Subtotal = $551,078

Issue Date FY: 2009 ( Subtotal = $541,871 )
2009	2009	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	6/10/2009	NON-COMPETING CONTINUATION	$541,871
														Subtotal = $541,871

Issue Date FY: 2008 ( Subtotal = $475,782 )
2008	2008	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	18	5/23/2008	NON-COMPETING CONTINUATION	$475,782
														Subtotal = $475,782

Issue Date FY: 2007 ( Subtotal = $472,197 )
2007	2007	CBR INSTITUTE FOR BIOMEDICAL RESEARCH INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	17	6/1/2007	NON-COMPETING CONTINUATION	$472,197
														Subtotal = $472,197

Issue Date FY: 2006 ( Subtotal = $473,500 )
2006	2006	CBR INSTITUTE FOR BIOMEDICAL RESEARCH INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	16	5/23/2006	COMPETING CONTINUATION	$473,500
														Subtotal = $473,500

Issue Date FY: 2005 ( Subtotal = $473,000 )
2005	2005	CBR INSTITUTE FOR BIOMEDICAL RESEARCH INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	3/14/2005	NON-COMPETING CONTINUATION	$473,000
														Subtotal = $473,000

Issue Date FY: 2004 ( Subtotal = $473,000 )
2004	2004	CENTER FOR BLOOD RESEARCH, INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	14	3/10/2004	NON-COMPETING CONTINUATION	$473,000
														Subtotal = $473,000

Issue Date FY: 2003 ( Subtotal = $425,700 )
2003	2003	CENTER FOR BLOOD RESEARCH, INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13		NON-COMPETING CONTINUATION	$425,700
														Subtotal = $425,700

Issue Date FY: 2002 ( Subtotal = $425,700 )
2002	2002	CENTER FOR BLOOD RESEARCH, INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	12	5/13/2002	NON-COMPETING CONTINUATION	$425,700
														Subtotal = $425,700

Issue Date FY: 2001 ( Subtotal = $450,700 )
2001	2001	CENTER FOR BLOOD RESEARCH, INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	11	3/29/2001	COMPETING CONTINUATION	$450,700
														Subtotal = $450,700

Issue Date FY: 2000 ( Subtotal = $387,234 ) (Continued on the next page)
Grand Total All Awards = $14,120,291

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Signal transduction and gene induction in lymphocytes

Award Number: R01AI040127

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1991

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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