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Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy

Award Number: R37CA249085
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy - Despite the positive impact that checkpoint inhibitor immunotherapy has had on the field of oncology, the majority of our cancer patients do not respond to this treatment strategy. It is clear that a more complete understanding of these mechanisms driving resistance to checkpoint inhibitor immunotherapy will lead to the development of more effective immunotherapy regimens and to improved patient selection for specific therapies. However, our understanding of active tumor- mediated resistance mechanisms that are more responsive to pharmacologic targeting remains poor. Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive cell population that have been correlated with inferior responses to checkpoint inhibitor therapy. Using pre-clinical models of different tumor types as well as clinical specimens harvested from melanoma patients, we have found that resistance to anti-PD-1 antibody (ab) immunotherapy is associated with the recruitment of granulocytic MDSCs (PMN-MDSCs) into the tumor bed. Subsequent mechanistic studies were conducted to understand the molecular underpinnings for this accumulation of PMN- MDSCs in tumors undergoing checkpoint inhibitor immunotherapy which noted that CXCR2- dependent chemokines are upregulated in response to a Wnt5a-YAP1 signaling axis and that this pathway is triggered by the release of heat shock protein-70 (HSP70) by tumors in response to CD8+ T cell activation. Using a genome-wide CRISPR screen, we have determined that the tumor NLRP3 inflammasome is essential for the induction of this signaling cascade and the ultimate recruitment of PMN-MDSCs to the tumor bed. Based on this cumulative data, we hypothesize that the adaptive recruitment of PMN-MDSCs and its subsequent suppression of effector T cell activity in response to anti-PD-1 ab immunotherapy is mediated by activation of the tumor NLRP3 inflammasome via tumor intrinsic PD-L1 signaling. We further propose that the pharmacologic inhibition of the NLRP3 inflammasome will enhance the efficacy of anti-PD-1 ab immunotherapy in an autochthonous model of BRAFV600E melanoma and that genetic mutations impacting this pathway can lead to differential responses to checkpoint inhibitor immunotherapy. In addition to modeling specific gain-of-function NLRP3 mutations in pre-clinical melanoma models, we will also leverage an ongoing clinical protocol designed to harvest tissue specimens from melanoma patients, enabling the association of NLRP3 genetic mutations and expression levels, PMN-MDSC tumor infiltration, and clinical response to checkpoint inhibitor immunotherapy. Overall, this study promises to contribute significantly to our understanding of adaptive resistance to anti-PD- 1 ab immunotherapy in 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: 2024 ( Subtotal = $308,487 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	5	8/1/2024	NON-COMPETING CONTINUATION	$308,487
														Subtotal = $308,487

Issue Date FY: 2023 ( Subtotal = $327,396 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	4	7/25/2023	NON-COMPETING CONTINUATION	$327,396
														Subtotal = $327,396

Issue Date FY: 2022 ( Subtotal = $452,808 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	3	7/22/2022	NON-COMPETING CONTINUATION	$320,179
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	3	7/25/2022	SUPPLEMENT FOR EXPANSION	$132,629
														Subtotal = $452,808

Issue Date FY: 2021 ( Subtotal = $515,041 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	003	2	8/5/2021	SUPPLEMENT FOR EXPANSION	$132,629
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	1	5/25/2021	SUPPLEMENT FOR EXPANSION	$60,897
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	002	2	7/29/2021	NON-COMPETING CONTINUATION	$321,515
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	1	5/26/2021	NEW	$0
														Subtotal = $515,041

Issue Date FY: 2020 ( Subtotal = $317,373 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	1	5/5/2020	NEW	$317,373
														Subtotal = $317,373

Grand Total All Awards = $1,921,105

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Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapy

Award Number: R37CA249085

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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