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Role of type 2 immune response in pancreatic cancer tumorigenesis

Award Number: R01CA262822
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Role of type 2 immune response in pancreatic cancer tumorigenesis - Project Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells remain largely unexplored. In a recent study, we demonstrated that cytokines, IL4 and IL13, secreted by TH2 cells (a subtype of CD4+ T cells), provide trophic support for PDAC development. Mechanistically, inhibiting this cytokine mediated crosstalk between cancer-TH2 cells either genetically or pharmacologically drastically reduces tumor growth and increases survival in a preclinical model. Our subsequent preliminary work identified a potent inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2 and other immune cells such as innate lymphoid cells 2 (ILC2) and Tregs. Importantly, we found that the release of IL33 by PDAC cells is mediated by intratumor mycobiome. Inhibition of IL33 or anti-fungal treatment leads to a decrease in the infiltration and activation of type 2 immune cells (TH2 and ILC2) and Treg cells, accompanied by significant PDAC tumor regression. Taking these observations together, we hypothesize that type 2 immune response plays an important role in PDAC tumorigenesis and intratumor mycobiome is key to the IL33 secretion. The major objective of this proposal is to elucidate the role of mycobiome in the IL33 mediated type 2 immune response and provide pre-clinical evidence to guide future clinical studies with an anti-IL33 monoclonal antibody in PDAC patients. To that end, we will determine the molecular mechanism of mycobiome mediated IL33 release in cell and organoid models of PDAC. Further, to conduct a clinically relevant study, we will analyze IL33, intratumor mycobiome and type 2 immunocytes in the PDAC patient tumor and serum samples. While our preliminary studies using the syngeneic orthotopic model have shown a significant tumor regression upon IL33 deletion or anti-fungal treatment, synergistic combination strategies are expected to be even superior in efficacy. So, we propose to use an anti-IL33 antibody in combination with anti-fungal treatment for superior efficacy. Finally, to block the IL33-TH2/ILC2 axis we have three genetically engineered mouse models that will allow rigorous testing of the function of IL33 in PDAC tumorigenesis. In conclusion, our study is poised to identify a novel strategy to target PDAC patients and provide mechanistic insights for future clinical development of anti- IL33 therapy.


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: 2025 ( Subtotal = $475,948 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	5	8/5/2025	SUPPLEMENT FOR EXPANSION	$71,398
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	5	7/17/2025	NON-COMPETING CONTINUATION	$404,550
														Subtotal = $475,948

Issue Date FY: 2024 ( Subtotal = $447,391 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	002	4	8/7/2024	SUPPLEMENT FOR EXPANSION	-$713
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	4	6/25/2024	NON-COMPETING CONTINUATION	$388,432
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	4	7/18/2024	SUPPLEMENT FOR EXPANSION	$59,672
														Subtotal = $447,391

Issue Date FY: 2023 ( Subtotal = $399,058 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	3	6/13/2023	NON-COMPETING CONTINUATION	$399,058
														Subtotal = $399,058

Issue Date FY: 2022 ( Subtotal = $415,258 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	001	2	8/31/2022	NON-COMPETING CONTINUATION	$8,306
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	2	7/8/2022	NON-COMPETING CONTINUATION	$406,952
														Subtotal = $415,258

Issue Date FY: 2021 ( Subtotal = $427,908 )
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	1	7/15/2021	NEW	$427,908
														Subtotal = $427,908

Grand Total All Awards = $2,165,563

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Role of type 2 immune response in pancreatic cancer tumorigenesis

Award Number: R01CA262822

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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