Contribution of the inflammasome to radiation response in pancreatic cancer

Ended Project Grant Awarded Last action

Award ID
K22CA251643
Recipient
Awarding agency
Obligated
$972,000

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date
Place of performance
Oregon, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The central theme of my postdoctoral fellowships has been to investigate mechanisms by which myeloid cells are recruited and activated to promote inflammation and immunosuppression during cancer. Chronic inflammation is a recognized hallmark of carcinogenesis and my research focus is to identify critical inflammatory pathways for combinatorial therapeutic strategies, such that the immune system can be harnessed for antitumor immunity. My current research focus is on pancreatic cancer, which is largely resistant to chemotherapy, radiation therapy (RT), and immune checkpoint blockade. RT elicits an immunogenic cell death whereby resident and recruited leukocytes respond to damage-associated molecular patterns (DAMPS) released by dying cells. Macrophages are central mediators of this response and recognize DAMPS via innate adjuvant sensors, including the toll-like receptor (TLR)/MYD88 pathway. Specificity in this pathway is regulated by expression of various NFB subunits that homo- or heterodimerize to drive transcriptional pathways involved in immune activation or immune suppression. My current work is to understand how mertk-dependent upregulation of NFB P50 regulates macrophage immune suppression post-RT, and suppresses local antitumor immunity by rewiring macrophage response to adjuvant signals through MYD88 signaling. This proposal extends on these findings to test the central hypothesis that inflammasome activation in tumor- associated macrophages restricts RT-induced antitumor CD8+ T cell responses in pancreatic cancer. As the first step of inflammasome activation, MYD88 signaling regulates transcription of IL1 and IL18 while the second step involves additional activation of inflammasome receptors by factors released by dying cells in response to RT. Our preliminary data implicate inflammasome activation in macrophages as a critical mechanism regulating immunosuppression following RT. Thus, we aim to (1) determine the functional significance of inflammasome activation in RT-mediated tumor clearance and (2) identify inflammasome signatures and phenotypes in macrophages responding to RT and determine whether this signature correlates with poor outcomes in patients. Studies utilizing lineage-specific knockout mice will identify the cell types in which inflammasome activation occurs and its functional consequences on regulating CD8+ T cell responses in response to RT. My long-term career goal is to become an independent investigator studying dominant immune mechanisms regulating cancer development and how certain aspects of innate immunity impart barriers to effective therapeutic strategies, including both traditional cytotoxic and immune-based therapies. During the K22 award period I plan to gain additional training to expand my skill set in bioinformatics, statistics, lab management, and communication skills, and to develop my independent research program so that I may establish a record of independent research project grant program funding.

Transactions

Action Obligated Date
Amendment $0
Amendment $162,000
Amendment $162,000
Amendment $162,000
Amendment $162,000
Amendment $162,000
Original award $162,000

Quick answers

Who received award K22CA251643?

K22CA251643 was awarded to Providence Health & Services - Oregon by National Cancer Institute (National Institutes of Health) on February 1, 2022.

How much is award K22CA251643 worth?

$972,000 has been obligated on K22CA251643.

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