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ARGININE AVAILABILITY, MODULATED BY MDSC, REGULATES T CELL FUNCTION IN CANCER

Award Number: R01CA082689
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1999
PERIOD OF PERFORMANCE END DATE: 11/30/2013

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ARGININE AVAILABILITY, MODULATED BY MDSC, REGULATES T CELL FUNCTION IN CANCER - DESCRIPTION (provided by applicant): Myeloid-Derived Suppressor Cells (MDSC) expressing Arginase (ARG) 1 are potent inhibitors of T cell function in cancer. MDSC deplete L-Arginine (L-Arg) in serum and the tumor microenvironment, severely impairing anti- tumor responses. Work done in the preceding five years identified the mechanisms by which MDSC deplete L- Arg and has started to identify the molecular mechanisms by which L-Arg depletion causes T cell anergy. We found that MDSC expressing ARG 1 infiltrate tumors and deplete L-Arg by rapid incorporation through CAT transporters. This L-Arg-depleted environment causes a T cell cycle arrest by inhibiting cyclin D3 and cdk4 (but not cyclin D2 or cdk6), inhibits the production of IFNg (but not IL2), and blocks the expression of the T cell receptor z chain (CD3z), severely impairing T cell function. Inhibition of ARG 1 re-establishes proliferation, IFNg production, and CD3z expression, and triggers an anti-tumor response. These mechanisms were found in mice and patients with cancer. Our results therefore suggest that L-Arg depletion triggers the selective inhibition of specific genes important for effector functions of T cells, and not a generalized decrease in protein synthesis from nutrient starvation. The data also suggest that this phenomenon is caused by the activation of a checkpoint that mediates the inhibition of these effector mechanisms. Therefore, blocking this checkpoint may make T cells resistant to the anergizing/tolerizing effect of MDSC. The proposed research will identify the molecular mechanisms triggered by L-Arg depletion that inhibit the expression of genes and proteins necessary for T cell effector functions. We will demonstrate the importance of these mechanisms in tumor- bearing mice and cancer patients, and will design and test novel therapeutic approaches that combine the inhibition of MDSC with the protection of T cells from the tolerizing tumor microenvironment. PUBLIC HEALTH RELEVANCE: This proposed research will determine how Myeloid-Derived Suppressor Cells (MDSC) inhibit T cells and will test new therapies designed to enhance the potential of immunotherapy for cancer patients. Cancer vaccines and cytokines can be an important therapeutic approach for patients whose tumors have failed standard forms of treatment.


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: 2013 ( Subtotal = $227,896 )
2013	2013	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	13	11/21/2012	NON-COMPETING CONTINUATION	$121,221
2013	2013	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	13	5/9/2013	NON-COMPETING CONTINUATION	$106,675
														Subtotal = $227,896

Issue Date FY: 2012 ( Subtotal = $242,442 )
2012	2012	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	12	4/24/2012	NON-COMPETING CONTINUATION	$24,244
2012	2012	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	12	11/17/2011	NON-COMPETING CONTINUATION	$218,198
														Subtotal = $242,442

Issue Date FY: 2011 ( Subtotal = $242,442 )
2011	2011	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	11	5/11/2011	NON-COMPETING CONTINUATION	$17,496
2011	2011	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	11	11/3/2010	NON-COMPETING CONTINUATION	$224,946
														Subtotal = $242,442

Issue Date FY: 2010 ( Subtotal = $249,940 )
2010	2010	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	10	12/14/2009	NON-COMPETING CONTINUATION	$224,946
2010	2010	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	10	1/25/2010	NON-COMPETING CONTINUATION	$24,994
														Subtotal = $249,940

Issue Date FY: 2009 ( Subtotal = $249,940 )
2009	2009	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	9	3/27/2009	COMPETING CONTINUATION	$31,547
2009	2009	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	9	12/19/2008	COMPETING CONTINUATION	$218,393
														Subtotal = $249,940

Issue Date FY: 2007 ( Subtotal = $201,658 )
2007	2007	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	8	5/10/2007	SUPPLEMENT FOR EXPANSION	$201,658
														Subtotal = $201,658

Issue Date FY: 2006 ( Subtotal = $264,992 )
2006	2006	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	001	7	6/29/2006	SUPPLEMENT FOR EXPANSION	$22,332
2006	2006	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	8	8/3/2006	NON-COMPETING CONTINUATION	$242,660
														Subtotal = $264,992

Issue Date FY: 2005 ( Subtotal = $248,500 )
2005	2005	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	7	8/23/2005	NON-COMPETING CONTINUATION	$248,500
														Subtotal = $248,500

Issue Date FY: 2004 ( Subtotal = $248,500 )
2004	2004	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	6	7/21/2004	NON-COMPETING CONTINUATION	$248,500
														Subtotal = $248,500

Issue Date FY: 2003 ( Subtotal = $248,500 )
2003	2003	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	5	7/17/2003	NON-COMPETING CONTINUATION	$248,500
														Subtotal = $248,500

Issue Date FY: 2002 ( Subtotal = $248,500 )
2002	2002	LSU HEALTH SCIENCES CENTER/NIH	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	4	7/29/2002	COMPETING CONTINUATION	$248,500
														Subtotal = $248,500

Issue Date FY: 2001 ( Subtotal = $207,865 )
2001	2001	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	3	7/10/2001	NON-COMPETING CONTINUATION	$207,865
														Subtotal = $207,865

Issue Date FY: 2000 ( Subtotal = $201,812 )
2000	2000	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Biology Research	000	2	6/23/2000	NON-COMPETING CONTINUATION	$201,812
														Subtotal = $201,812

Issue Date FY: 1999 ( Subtotal = $510,599 )
1999	1999	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Indicates awards funded from multiple programs	000	1	7/19/1999	NEW	$510,599
														Subtotal = $510,599

Grand Total All Awards = $3,593,586

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ARGININE AVAILABILITY, MODULATED BY MDSC, REGULATES T CELL FUNCTION IN CANCER

Award Number: R01CA082689

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1999

PERIOD OF PERFORMANCE END DATE: 11/30/2013

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