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Targeting Chronic ER Stress in T Cells to Improve Cancer Immunotherapy

Award Number: R01CA244361
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeting Chronic ER Stress in T Cells to Improve Cancer Immunotherapy - PROJECT SUMMARY Sarcomas are an immunogenic tumor type replete with tumor antigen experienced CD8 tumor infiltrating lymphocytes (TILs). Surprisingly, checkpoint therapy that targets programmed cell death protein 1 (a-PD-1) to reinvigorate CD8 TILs is largely ineffective in sarcomas and has not gained FDA approval. CD8 TILs experience stress, but the stress response has not been widely studied in CD8 TILs of cancer patients. Under acute stress, endoplasmic reticulum (ER) stress sensor protein kinase R (PKR)-like ER kinase (PERK) protects cells. Under chronic stress, PERK activates a pro-apoptotic response that induces cell death. We previously demonstrated that PERK is detrimental to CD8 T cells in tumors. We now reveal robust preliminary data that indicate that the chronic PERK axis governed by activating transcription factor 4 (ATF4) and ER oxidoreductase 1 (ERO1a) shapes CD8 TIL fate in mouse and human sarcomas and impairs response to a-PD-1 therapy. Our data are intriguing given the role of PERK to protect cells under acute stress through attenuation of translation. Indeed, we found that the tumor microenvironment is a form of acute stress that inhibits translation in CD8 T cells through PERK. However, in vivo in the presence of tumor antigen, the chronic arm of the PERK response appears to dictate PD-1+ CD8 TIL fate. This proposal will formally test that chronic targets ATF4 and ERO1a drive activation and metabolic exhaustion in CD8 TILs that limit the efficacy of a-PD-1 therapy, while the acute PERK response protects CD8 TILs under sarcoma microenvironment stress. To accomplish our aims we have developed unique genetic mouse models to analyze the T cell-specific contributions of the chronic and acute phases of the stress response to shape efficacy of a-PD-1 therapy in sarcomas. In Aim 1, we will use LckcreRosa26-ATF4loxtg mice with T cell-specific overexpression of human ATF4 and CD8 TILs from sarcoma patients to determine the contribution of ATF4 to drive activation and exhaustion in CD8 TILs and shape response to a-PD-1 therapy in sarcomas. The results are expected to reframe and advance our understanding of T cell exhaustion in sarcomas. In Aim 2 we have created unique ERO1a-/- mice to formally define how ERO1a affects CD8 TIL metabolic exhaustion and response to a-PD-1 therapy and we will use CD8 TILs from sarcoma patients to study the contribution of ERO1a to human TIL exhaustion. The results are expected to produce a robust molecular target that holds fantastic potential to improve the efficacy of a-PD-1 therapy in cancer patients. In Aim 3 we will use our LckcrePERKf/f mice and Eif2aS51A mutant mice to elucidate requirements of the acute stress response in CD8 TILs. The results are expected to shape the direction of drug development surrounding the ER stress response in cancer immunotherapy. Successful completion of this proposal will identify radical new chronic ER stress targets that undermine the widespread success of immunotherapy in sarcoma patients and establish a new paradigm that informs drug development for all solid tumor 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: 2026 ( Subtotal = -$12,624 )
2026	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	6	11/19/2025	NON-COMPETING CONTINUATION	-$12,624
														Subtotal = -$12,624

Issue Date FY: 2024 ( Subtotal = $415,535 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	001	6	6/17/2024	SUPPLEMENT FOR EXPANSION	$82,870
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	6	6/14/2024	NON-COMPETING CONTINUATION	$332,665
														Subtotal = $415,535

Issue Date FY: 2023 ( Subtotal = $458,508 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	003	5	8/15/2023	SUPPLEMENT FOR EXPANSION	$87,216
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	002	5	8/1/2023	NON-COMPETING CONTINUATION	$345,558
2023	2021	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	2	11/23/2022	NON-COMPETING CONTINUATION	$9,351
2023	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	001	3	1/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$16,383
														Subtotal = $458,508

Issue Date FY: 2022 ( Subtotal = $349,947 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	003	4	5/20/2022	NON-COMPETING CONTINUATION	$349,947
2022	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	001	3	2/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$190,375
2022	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	2	2/16/2022	NON-COMPETING CONTINUATION	-$190,375
2022	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	002	2	3/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,947

Issue Date FY: 2021 ( Subtotal = $340,760 )
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	2	5/28/2021	NON-COMPETING CONTINUATION	$340,760
														Subtotal = $340,760

Issue Date FY: 2020 ( Subtotal = $348,281 )
2020	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Biology Research	000	1	5/14/2020	NEW	$348,281
														Subtotal = $348,281

Grand Total All Awards = $1,900,408

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Targeting Chronic ER Stress in T Cells to Improve Cancer Immunotherapy

Award Number: R01CA244361

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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