Thursday, November 21, 2024 11/21/2024

Investigating the Role of Radiation-induced Cell Death in Innate Lymphoid Cell Activation within Unique Tumor Microenvironments

Award Number: R00CA256526
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY: The role of ionizing radiation as an “in situ” vaccine is based on radiation’s ability to induce the release of tumor antigens which activate antigen-presenting cells to prime CD8+ T cells. This mediates the “abscopal effect” in which radiation to one tumor leads to eradication of a distant tumor. However, clinical reports of the “abscopal effect” are rare, possibly because radiation can promote the generation of immunosuppressive cells. While radiation has been used therapeutically for over a century, it is still poorly understood which types of cell death are induced by different types of radiation regimens and how these mechanisms of cell death effect the inflammatory milieu and anti-tumor immunity. Interestingly, while T cells are very sensitive to apoptosis, but tissue-resident innate lymphoid cells (ILC) are radioresistant. Group 1, 2 and 3 ILCs are activated by specific members of the IL-1 family of cytokines which serve as “alarmins” of tissue damage. However, the precise contribution of cell death to IL-1 cytokine release and downstream immune responses has not been well characterized, and ILC have never been implicated in the immune response to radiation. Therefore, the proposed experiments will address critical gaps by examining how radiotherapy-induced mechanisms of cell death release specific IL-1 family cytokines in the tumor micorenvironment to activate various ILC subsets (Aim 1). The K99 mentored experiments will involve the integration of patient derived organoids, cell death assays, and novel orthotopic murine tumor models, as well as knockout mice for various cytokines. Results from Aim 1 will lead to subsequent R00 independent phase investigations to determine how radiation-induced immune responses regulate the balance between anti-tumor immunity (Aim 2) and radiation-induced pneumonitis and fibrosis (Aim 3). Aim 3 will build on my doctoral work generating the IL-22-IRES-BFP reporter mouse to study the role of this ILC3-induced cytokine in radiation-induced fibrosis. Collectively, the research will yield unprecedented insight into how radiation-induced cell death mechanisms and specific cytokines direct downstream immune responses and clinical outcomes. The technical training and career development obtained during the R99 phase will help me to launch my independent research program and reveal additional questions for future investigation. Results from this work will serve as preliminary data for a translational study to investigate if there is a correlation between radiation-induced cell death, release of IL-1 cytokine family members, immune cell activation, and clinical outcomes. Given my comprehensive training and experience in both immunology and radiation oncology, I am uniquely positioned to utilize both skillsets to address important questions at the intersection of these fields and gain fundamental understanding of the mechanisms that underlie the efficacy of radiation 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: 2024 ( Subtotal = $249,000 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	3/12/2024	NON-COMPETING CONTINUATION	$224,099
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$24,901
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	000	3	3/21/2023	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	000	2	11/30/2021	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	003	2	7/1/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	002	2	1/3/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	001	2	12/7/2021	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Grand Total All Awards = $747,000

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Investigating the Role of Radiation-induced Cell Death in Innate Lymphoid Cell Activation within Unique Tumor Microenvironments

Award Number: R00CA256526

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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