Wednesday, December 17, 2025 12/17/2025

Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria

Award Number: R01CA269902
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria - Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise in young people. Colorectal tumors are often detected at late stages where therapy often fails. Immunotherapy is revolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients. Thus, there is a critical need for improved therapies for CRC. Colorectal tumors grow from the intestinal epithelium and interact with the colonic microbiota. CRC has been associated with shifts in the composition of the microbiota that promote inflammation and tumor growth. The microbiota can also shape colonic T and B cell immune responses and is a critical modulator of the efficacy of tumor immunotherapy. Using a mouse model of CRC (AOM/DSS) we show that colonization with a single bacterial taxon: Helicobacter hepaticus, after tumors have already developed, leads to a reduction in tumor burden and size. H. hepaticus also increased the number, size and organization of Tertiary lymphoid structures (TLS) next to colorectal tumors. The presence of TLS is associated with positive outcomes in CRC patients, but how they act to increase anti-tumor immunity is not known. H. hepaticus-dependent tumor reduction depended upon CD4 T cells and B cells but not CD8 T cells. Most H. hepaticus-specific CD4+ T cells differentiated into T Follicular Helper (TFH) cells and localized in TLS. Importantly, CD4cre Bcl6flox mice, that cannot form TFH cells, also failed to either form TLS or control CRC growth, but transfer of H. hepaticus-specific CD4+ T cells completely restored the anti-tumor response. Our hypothesis is that the distinct mucus colonization properties of Hhep leads to activation of anti-Hhep TFH that interact with B cells to induce peri-tumoral TLS formation. Colonic TLS then act as platforms for the activation of anti-tumor CD4+ T cells, NK cells and B cells which invade the tumor to support effective anti-tumor immunity. We will test this hypothesis in two aims. First, we will identify the genes and behavior, (such as mucus/epithelial colonization) associated with Helicobacter-associated control over CRC. Next we will correlate the presence of TLS, TFH and B cells in human CRC patients with specific mucus and tumor resident bacteria. Finally, we will use our mouse models to identify whether TLS serve as platforms for more effective activation of anti-tumor T and B cells. Together, our proposal has the potential to identify the key bacterial components that should be targeted to augment anti-tumor immunity and colonic TLS. Further we may identify mechanisms by which TLS support anti- tumor immune responses which could be used to formulate therapeutic anti-CRC approaches. If successful we could identify mechanisms to rationally modify the microbiome to increase anti-tumor immunity.


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 = $503,559 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	4	12/11/2025	NON-COMPETING CONTINUATION	$503,559
														Subtotal = $503,559

Issue Date FY: 2025 ( Subtotal = $563,882 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	002	3	6/4/2025	NON-COMPETING CONTINUATION	$56,388
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	001	3	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	3	11/21/2024	NON-COMPETING CONTINUATION	$507,494
														Subtotal = $563,882

Issue Date FY: 2024 ( Subtotal = $535,501 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	$507,316
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$28,185
														Subtotal = $535,501

Issue Date FY: 2023 ( Subtotal = $578,243 )
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	11/21/2022	NEW	$578,243
														Subtotal = $578,243

Grand Total All Awards = $2,181,185

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Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria

Award Number: R01CA269902

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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