PROJECT SUMMARY/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 NF¿B 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 NF¿B 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.