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Dissecting the source and mechanisms of IL-17-mediated modulation of pancreatic tumorigenesis

Award Number: R37CA237384
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Dissecting the source and mechanisms of IL-17-mediated modulation of pancreatic tumorigenesis - Abstract The incidence of pancreatic adenocarcinoma (PDAC) is steadily increasing while most treatment modalities remain ineffective. Therefore, it would not be a surprise to learn that PDAC is one of the top-4 causes of cancer- related mortality. What is most striking about this malignancy is that even if detected at early stages, outcomes remain poor. It is well known that pancreatic cancer is characterized by an immunosuppressive environment, already found surrounding premalignant lesions or pancreatic intraepithelial neoplasia (PanIN), which has been postulated as one of the main reasons for the lack of response to most therapies. However, the regulatory signals that precede and support the development of this suppressive TME are not well characterized. The objective of this grant is to characterize the mechanisms and regulators implicated in the generation of the immunosuppressive TME that characterizes pancreatic tumorigenic process and to reverse it through pharmacological and microbial interventions. Our laboratory found that IL-17-secreting immune cells play an important role in promoting pancreatic tumorigenesis in genetically engineered mouse (GEMM) models of pancreatic cancer. We now plan to characterize the mechanisms by which IL-17 promotes tumorigenesis by genetically deleting the IL-17 receptor specifically from the pancreatic oncogenic epithelium using GEMM and CRISPR/Cas9 (Aim 1). We also found that IL-17 neutralization decreases recruitment of myeloid cells, mostly neutrophils, and induces CD8+T cells activation and in PDAC orthotopic model. Monoclonal antibodies against IL-17 or neutrophils will be used to assess the mechanisms employed by IL-17 supporting an immunosuppressive TME (Aim 2). Finally, we have recently found that fecal microbial transplants can modulate tumors systemically. In particular, human PDAC-associated gut bacteria is capable of increasing IL-17 levels in circulation, which may affect distant tumors like pancreatic cancer. We now plan to definitively address the role gut bacteria in promoting Th17 differentiation and its systemic implications by performing human-into-mice fecal microbial transplants (Aim 3). Achieving our goals will not only help us better understand immunological as well as microbial mechanisms implicated in pancreatic tumorigenesis, but will also result in practical novel interventions with either monoclonal antibodies, narrow spectrum antibiotics or microbial transplants that would have a direct impact in preventing and/or treating this deadly disease.


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 = $0 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	11/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $748,012 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	9/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$748,012
														Subtotal = $748,012

Issue Date FY: 2024 ( Subtotal = $352,047 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	6/27/2024	NON-COMPETING CONTINUATION	$352,047
														Subtotal = $352,047

Issue Date FY: 2023 ( Subtotal = $363,164 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	6/21/2023	NON-COMPETING CONTINUATION	$363,164
														Subtotal = $363,164

Issue Date FY: 2022 ( Subtotal = $370,575 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	7/18/2022	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $370,575

Issue Date FY: 2021 ( Subtotal = $370,575 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	6/15/2021	NON-COMPETING CONTINUATION	$370,575
2021	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	6/7/2021	NEW	$0
														Subtotal = $370,575

Issue Date FY: 2020 ( Subtotal = $370,575 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	9/18/2020	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $2,574,948

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Dissecting the source and mechanisms of IL-17-mediated modulation of pancreatic tumorigenesis

Award Number: R37CA237384

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/18/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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