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Transcriptional co-activator PGC-1α promotes anti-tumor immunity in colorectal cancer

Award Number: R21CA300890
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/05/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Transcriptional co-activator PGC-1α promotes anti-tumor immunity in colorectal cancer - Project Summary (30 lines) Transcriptional coactivator PGC-1α safeguards against many diseases, including some cancers. PGC-1α’s anti- tumor activity has been linked to its ability to modulate energy metabolism in cancer and stromal cells. Here, we posit that cancer-cell PGC-1α also inhibits tumor progression by promoting anti-tumor immunity, which ~90% of colorectal cancer (CRC) tumors escape. Mining human genomic datasets, we have found that PGC-1α is downregulated in most CRC tumors, and that lower PGC-1α tumor levels correlate with poorer survival in patients with one of two specific tumor subtypes, which together account for 50% of cases: ‘hot’ immune-active CMS1 tumors, which may develop an immunosuppressive microenvironment; and ‘cold’ immune-desert CMS2 tumors. We hypothesize that PGC-1α gene addition therapy could reduce the resistance of hot tumors to immune checkpoint inhibitor (ICI) immunotherapy, and turn cold tumors into hot tumors, thereby sensitizing them to ICIs. We have published that PGC-1α activates immunity genes via what we called its “Cap-Binding Protein 80- Binding Motif” (CBM). CBM-activated genes encode proteins that promote three anti-tumor immunity axes: (i) the chemoattractants CCL5 and CXCL10, which promote tumor infiltration by CD8+ cytotoxic T lymphocytes (CTLs); (ii) the immunoproteasome factors PSMB8/9, the antigen-processing factors TAP1/2 and ERAP, and the MHC-I transactivator NLRC5, which enable processing and presentation of tumor antigens to activate CTLs; and (iii) LGALS3BP and GBPs, which may modulate the tumor immune microenvironment to support anti-tumor immunity. PGC-1α also activates via its CBM the genes encoding the immune checkpoint proteins PD-L1 and Gal9, which are often counteracted by ICI immunotherapy. We found that radiotherapy induces these immune genes more efficiently in cold CRC tumors expressing ‘high’ PGC-1α levels, indicating that increasing PGC-1α tumor expression may improve therapeutic efficacy. Accordingly, we have shown that expression of PGC-1α activates many of those genes in two relevant CRC mouse lines in which it is repressed: (i) KAP cells, which were recently developed by our research team and represent a novel mouse model of cold CRC, and, to a lesser extent, (ii) MC38 cells, which constitute a well- established mouse model of hot CRC. We aim to elucidate the anti-tumor immunity role of PGC-1α as follows: Aim 1: We propose to use Cas9n to introduce in KAP and MC38 cells an inducible transgene encoding wild- type PGC-1α, a PGC-1α variant in which the CBM is mutated, or eGFP as a negative control. Aim 2: RNA-seq will identify the full PGC-1α-dependent gene expression networks in the cancer cells of KAP- and MC38-derived orthotopic tumors and determine CBM dependence. We will then use genetic screens to identify which immune genes contribute most to PGC-1α’s anti-tumor activity, and determine how. Aim 3: We will test if inducible expression of PGC-1α in cancer cells dampens CRC tumor growth and improves survival in a CBM-dependent manner and in synergy with ICI immunotherapy and radiotherapy .


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 = $388,901 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Cancer Biology Research	000	1	6/9/2026	NEW	$388,901
														Subtotal = $388,901

Grand Total All Awards = $388,901

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Transcriptional co-activator PGC-1α promotes anti-tumor immunity in colorectal cancer

Award Number: R21CA300890

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/05/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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