Author ORCID Identifier
0000-0003-3642-2144
Date of Graduation
5-2023
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Florencia McAllister, MD
Committee Member
Menashe Bar-Eli, PhD
Committee Member
Jennifer Bailey-Lundberg, PhD
Committee Member
Pamela L. Wenzel, PhD
Committee Member
Yi Xu, PhD
Abstract
Cancer is a rising cause of mortality worldwide. Microbiota is the collection of micro-organisms that live inside our bodies and can impact the host health and disease by interacting with the immune and metabolic systems. The relationship between the microbiota and cancer is complex. Gut and intratumoral microbiota can affect cancer development and progression by influencing patient outcomes and therapy responsiveness in several cancer types. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment (TME) which limits efficacy of most available therapies. The tumoral niche provides a privileged microenvironment for microbial colonization that can in turn mediate local effects on the cells in the TME. We previously reported that long-term survival in PDAC is associated with an intratumoral microbial signature and demonstrated the functional role of transplantable PDAC gut microbiota in affecting tumor immunity and growth. However, the crosstalk between microbes in the gut and tumors, immunogenic potential of selected microbes and host microbial crosstalk remains unknown.
To interrogate the microbial niche within tumors, we examined microbial distribution patterns inside different tumor types using novel qualitative and quantitative imaging methodologies. We assessed the effect of microbial burden on transcriptomic changes in tumor and neighboring cells in PDAC through two independent spatial transcriptomic approaches. These analyses revealed that tumoral IL-17 signaling was enriched in the presence of tumor cells with high microbial burden. IL-17/IL-17RA signaling pathway is essential for microbial regulation and maintaining mucosal immunity. IL-17 can be stimulated by commensal bacteria under normal physiological conditions and has been shown to promote early pancreatic tumors by inducing a stemness signature. Both IL-17 neutralization and antibiotics reduce murine PDAC growth. We evaluated the role of microbially driven IL-17 signaling during PDAC development. We found that PDAC development led to a concomitant increase in intestinal IL-17 signaling downstream of microbial changes. Compartmental genetic deletion of IL-17RA in implantable syngeneic mouse models of PDAC identified the role of gut epithelial IL-17RA signaling in maintaining microbial homeostasis. Disruption of intestinal IL-17RA signaling systemically increased IL-17 development which triggered protumorigenic B cells. Based on these findings of microbial-IL-17 signaling axis in promoting tumor growth, we targeted the IL-17 signaling pathway during advanced cancer to evaluate its role on tumor growth and TME organization. We found that IL-17 signaling recruits protumorigenic neutrophils into the TME which undergo a pathogen clearance mechanism called Neutrophil Extracellular Trap formation (NETosis) that spatially excluded cytotoxic CD8 T cells. Blockade of IL-17/IL-17RA signaling, neutrophils or NETosis synergized with immunotherapy to reduce advanced PDAC tumor growth.
Overall, in this dissertation, we provide novel insights into the functional role of the microbiota in influencing host cellular signaling and identify novel avenues for combinatorial microbial and immunotherapeutic approaches.
Keywords
microbiome; pancreatic cancer; IL-17; B cells; NETosis; spatial transcriptomics; immunotherapy
Included in
Cancer Biology Commons, Environmental Microbiology and Microbial Ecology Commons, Immunity Commons