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Defining how obesity shapes immunity and the success of cancer immunotherapy

Award Number: R01CA238705
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Defining how obesity shapes immunity and the success of cancer immunotherapy - NCI Provocative Question #2: “How do variations in immune function caused by comorbidities or observed among different populations affect response to cancer therapy?” The success of checkpoint blockade immunotherapy and its role in the future of cancer treatment is now beyond debate, but durable responses still only occur in a subset of patients. Extending the success of immunotherapy to a broader range of patients requires new insight into the variables that dictate therapeutic success and failure. More than a third of Americans are now considered obese, a condition associated with impaired immune responses to infections and vaccines, and a greater risk of developing some types of cancer. This implies a potential link between obesity and poor tumor immunity, which has been documented in a few preclinical studies but mechanistic insight remains sparse. More importantly, efforts to understand how obesity influences outcomes in human cancer patients has been mired by conflicting results and limited metrics such as body mass index (BMI) to measure obesity in people. These inconsistencies have contributed to the controversial “obesity paradox”, which suggests that obesity has a positive impact on outcomes for patients with cancer, cardiovascular disease or a host of other ailments, but this idea is facing mounting skepticism. Our preliminary research in a mouse tumor model refutes the obesity paradox, identifying obesity as a barrier to the success of cancer immunotherapy. Here, obesity was associated with poor control of melanoma tumor growth following checkpoint blockade immunotherapy, associated with dysfunction of tumor infiltrating T cells. We hypothesize that obesity-related comorbidities such as excessive adipose tissue, inflammation, altered metabolism and liver function compromise immunotherapy by suppressing the functional restoration of T cells. To test this, we will employ several innovative mouse models that allow discrete manipulation of T cell effector pathways (Aim 1), excessive adiposity and the development of fatty liver disease (Aim 2). These mechanistic studies will enable the contributions of individual comorbidities to be rigorously dissected. We predict that results from these animal experiments will enable parallel discoveries in cancer patients (Aim 3), revealing the critical components of human obesity that influence outcomes during cancer immunotherapy. Our goal is to define the complex obesity-related factors that shape immune responses to cancer and influence outcomes during cancer immunotherapy. Given the magnitude of the obesity epidemic, our translational research has the potential to benefit a significant number of cancer patients for whom current immunotherapies may have limited efficacy and require refined treatment approaches.


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 = -$5,560 )
2025	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	5	12/4/2024	NON-COMPETING CONTINUATION	-$5,560
														Subtotal = -$5,560

Issue Date FY: 2023 ( Subtotal = $339,625 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	5	7/20/2023	NON-COMPETING CONTINUATION	$339,625
														Subtotal = $339,625

Issue Date FY: 2022 ( Subtotal = $339,625 )
2022	2022	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	4	7/31/2022	NON-COMPETING CONTINUATION	$339,625
														Subtotal = $339,625

Issue Date FY: 2021 ( Subtotal = $346,556 )
2021	2021	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	3	7/12/2021	NON-COMPETING CONTINUATION	$346,556
														Subtotal = $346,556

Issue Date FY: 2020 ( Subtotal = $346,556 )
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	2	6/26/2020	NON-COMPETING CONTINUATION	$346,556
														Subtotal = $346,556

Issue Date FY: 2019 ( Subtotal = $346,556 )
2019	2019	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	1	7/31/2019	NEW	$346,556
														Subtotal = $346,556

Grand Total All Awards = $1,713,358

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Defining how obesity shapes immunity and the success of cancer immunotherapy

Award Number: R01CA238705

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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