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Investigating CREB5-driven mechanisms of immune therapy resistance

Award Number: R01CA285582
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/11/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Investigating CREB5-driven mechanisms of immune therapy resistance - Project Summary: Treatment with immune checkpoint inhibitors induce remarkable clinical responses in several cancer types. However, most cancer patients do not respond to immunotherapy, and patients who initially respond often exhibit acquired resistance. Understanding the universe of immune evasion strategies will enable the design of more effective immunotherapies. In preliminary studies, we identified genes that drive immune evasion by performing a genome scale in vivo CRISPR gain-of-function screen in tumors treated with anti-PD-1 antibodies; and discovered the transcription factor CREB5 as a top resistance mediator. We found CREB5 overexpressing tumors exhibit poor responses to anti-PD-1 and have fewer infiltrating CD8+ T cells. Using transcriptional profiling, we showed CREB5 drives upregulation of extracellular matrix genes including collagen and collagen- stabilizing factors. Collagen is the major ligand for the inhibitory receptor LAIR1, which is broadly expressed on T cells, B cells, NK cells, and myeloid cells. Deletion of LAIR1 in mice or overexpression of the decoy receptor LAIR2 in tumors abrogates the resistance-causing effect of CREB5 overexpression, suggesting that CREB5 overexpression drives resistance via collagen-LAIR1 inhibitory signaling. These observations form the foundation of our proposed studies to decipher the role of this tumor intrinsic mechanism of resistance to immune checkpoint therapy. Specifically, we propose to understand: 1) the molecular mechanisms governing CREB5 regulation and transcription; 2) CREB5-interacting proteins that drive collagen matrix deposition; and 3) the mechanism(s) by which LAIR1-collagen sensing inhibits anti-tumor immune responses. These studies will not only advance our understanding of immune regulation but will also provide new insights and targets useful for the development of new immunotherapy approaches for 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: 2026 ( Subtotal = $610,472 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	000	2	1/15/2026	NON-COMPETING CONTINUATION	$549,425
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	001	2	4/16/2026	NON-COMPETING CONTINUATION	$61,047
														Subtotal = $610,472

Issue Date FY: 2025 ( Subtotal = $620,820 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Biology Research	000	1	12/11/2024	NEW	$620,820
														Subtotal = $620,820

Grand Total All Awards = $1,231,292

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Investigating CREB5-driven mechanisms of immune therapy resistance

Award Number: R01CA285582

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/11/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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