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Principal Investigator: Prasenjit Dey
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2024
Award: $58,959
Funding agency: National Cancer Institute
Project Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that remains largely
incurable. Although the cause for this profound therapeutic resistance is poorly understood, it is however partly
blamed on signaling factors present in the tumor microenvironment (TME), which supports the proliferation and
survival of neoplastic cells. Apart from being stroma rich, PDAC TME is associated with a distinctive tumor
immune infiltrate. Paradoxically, most immunotherapy trials using immune checkpoint inhibitors, either as
monotherapy or combination, failed to increase patient survival motivating exploration of new therapeutic
strategies. To that end, the cytokine mediated heterotypic interactions between cancer cells and immune cells
remain largely unexplored. In a recent study, we demonstrated that cytokines, IL4 and IL13, secreted by TH2
cells (a subtype of CD4+ T cells), provide trophic support for PDAC development. Mechanistically, inhibiting this
cytokine mediated crosstalk between cancer-TH2 cells either genetically or pharmacologically drastically reduces
tumor growth and increases survival in a preclinical model. Our subsequent preliminary work identified a potent
inflammatory cytokine, IL33 which is overexpressed and released by PDAC cells that attract and activate TH2
and other immune cells such as innate lymphoid cells 2 (ILC2) and Tregs. Importantly, we found that the release
of IL33 by PDAC cells is mediated by intratumor mycobiome. Inhibition of IL33 or anti-fungal treatment leads to
a decrease in the infiltration and activation of type 2 immune cells (TH2 and ILC2) and Treg cells, accompanied
by significant PDAC tumor regression. Taking these observations together, we hypothesize that type 2 immune
response plays an important role in PDAC tumorigenesis and intratumor mycobiome is key to the IL33 secretion.
The major objective of this proposal is to elucidate the role of mycobiome in the IL33 mediated type 2 immune
response and provide pre-clinical evidence to guide future clinical studies with an anti-IL33 monoclonal antibody
in PDAC patients. To that end, we will determine the molecular mechanism of mycobiome mediated IL33 release
in cell and organoid models of PDAC. Further, to conduct a clinically relevant study, we will analyze IL33,
intratumor mycobiome and type 2 immunocytes in the PDAC patient tumor and serum samples. While our
preliminary studies using the syngeneic orthotopic model have shown a significant tumor regression upon IL33
deletion or anti-fungal treatment, synergistic combination strategies are expected to be even superior in efficacy.
So, we propose to use an anti-IL33 antibody in combination with anti-fungal treatment for superior efficacy.
Finally, to block the IL33-TH2/ILC2 axis we have three genetically engineered mouse models that will allow
rigorous testing of the function of IL33 in PDAC tumorigenesis. In conclusion, our study is poised to identify a
novel strategy to target PDAC patients and provide mechanistic insights for future clinical development of anti-
IL33 therapy.
Terms: <A fumigatus><A. fumigatus><Agonist><Antibodies><Aspergillus fumigatus><Assay><B-Cell Stimulatory Factor 1 Gene><BSF-1 Gene><BSF1 Gene><Baculoviridae><Baculoviruses><Binding><Binding Sites><Bioassay><Biological Assay><Blood Serum><C albicans><C. albicans><C.albicans><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cancers><Candida albicans><Cell Body><Cell Communication and Signaling><Cell Line><Cell Nucleus><Cell Nucleus Active Transport><Cell Signaling><CellLine><Cells><Checkpoint inhibitor><Clinical Research><Clinical Study><Clinical Treatment Moab><Closure by Ligation><Combining Site><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasm><DKFZp547I0610><DKFZp564I0682><Data><Development><Disease><Disorder><ELISA><Electron Cryomicroscopy><Enzyme-Linked Immunosorbent Assay><Exocytosis><Future><GEM model><GEMM model><Genetically Engineered Mouse><Homolog of Drosophila TOLL><IL-13><IL-4 Gene><IL13><IL4><IL4 gene><Image><Immune><Immune Precipitation><Immune checkpoint inhibitor><Immune response><Immunes><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><Immunologic Receptors><Immunological Receptors><Immunological response><Immunoprecipitation><In Vitro><Incubated><Infiltration><Inflammatory><Interleukin-13><Interleukin-4 Gene><Interleukin-4 Precursor Gene><Intracellular Communication and Signaling><KIAA0012><Kinetics><Ligation><Location><Lymphoid Cell><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measurement><Measures><Mediating><Mediator><Medical Research><Modeling><Molecular><Molecular Biology Techniques><Molecular Interaction><Molecular Weight><Monoclonal Antibodies><Nuclear Transport><Nucleocytoplasmic Shuttling><Nucleus><Oncogenesis><Organoids><PDA model><PDAC Model><PDAC cancer cell><PDAC cell><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Plasmid Cloning Vector><Plasmid Vector><Play><Poly I-C><Polyinosinic-Polycytidylic Acid><Pre-Clinical Model><Preclinical Models><Production><Proliferating><Proteins><Reactive Site><Receptor Protein><Regulation><Regulatory T-Lymphocyte><Research Institute><Role><Sampling><Serum><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sodium Chloride><Stimulus><Strains Cell Lines><Structure><Surface Plasmon Resonance><System><T4 Cells><T4 Lymphocytes><TIL3><TIL4><TLR protein><TLR1><TLR1 gene><TLR1 protein><TLR1 receptor><TLR2><TLR2 gene><TLR2 receptor><TLR3><TLR3 gene><TLR4><TLR4 gene><TLR5><TLR5 gene><TLR5 receptor><TLR6><TLR6 gene><TLR6 receptor><TLR7><TLR7 gene><TLR8><TLR8 gene><Techniques><Testing><Th-2 Cell><Th2 Cells><Therapeutic><Therapeutic Fungicides><Time><Toll Homologue><Toll-Like Receptor 1><Toll-Like Receptor 2><Toll-Like Receptor 3><Toll-Like Receptor 5><Toll-Like Receptor 7><Toll-Like Receptor 8><Toll-Like Receptor Family Gene><Toll-Like Receptor Pathway><Toll-like receptor 6><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Toll/Interleukin-1 Receptor-Like><Toll/Interleukin-1 Receptor-Like Protein 3><Treg><Tumor Cell><Tumor-infiltrating immune cells><Type 2 Helper Cell><Universities><Vesicle><Western Blotting><Western Immunoblotting><Work><anti-fungal><anti-fungal agents><anti-fungal drug><biological signal transduction><cancer cell><cancer microenvironment><clinical development><clinical relevance><clinically relevant><cryo-EM><cryoEM><cryogenic electron microscopy><cultured cell line><cytokine><dectin 1><density><developmental><enzyme linked immunoassay><experience><fungal microbiome><fungal pathogen><fungi pathogen><fungus><genetically engineered mouse model><genetically engineered murine model><host response><imaging><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point inhibitor><immune receptor><immune system response><immunoresponse><immunotherapy trials><in silico><infiltration of tumors by immune cells><insight><intratumoral immune cell><intratumoral immune infiltrate><mAbs><malignancy><microbial><monoclonal Abs><mycobiome><neoplasm/cancer><neoplastic cell><neutralizing antibody><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleocytoplasmic transport><overexpress><overexpression><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pathogenic fungus><pathway><pharmacologic><poly I:C><poly IC><poly(I:C)><pre-clinical><preclinical><protein blotting><protein purification><protein structure><protein structures><proteins structure><receptor><regulatory T-cells><resistance to therapy><resistant to therapy><rsc786><salt><scale up><social role><therapeutic resistance><therapy resistant><toll-5 receptor><toll-like receptor 4><treatment resistance><tumor><tumor growth><tumor immune cell><tumor immune infiltrate><tumor infiltration of immune cells><tumor microenvironment><tumorigenesis><validation studies>