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Principal Investigator: Florencia McAllister
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $352,047
Funding agency: National Cancer Institute
Abstract
The incidence of pancreatic adenocarcinoma (PDAC) is steadily increasing while most treatment modalities
remain ineffective. Therefore, it would not be a surprise to learn that PDAC is one of the top-4 causes of cancer-
related mortality. What is most striking about this malignancy is that even if detected at early stages, outcomes
remain poor. It is well known that pancreatic cancer is characterized by an immunosuppressive environment,
already found surrounding premalignant lesions or pancreatic intraepithelial neoplasia (PanIN), which has been
postulated as one of the main reasons for the lack of response to most therapies. However, the regulatory signals
that precede and support the development of this suppressive TME are not well characterized. The objective of
this grant is to characterize the mechanisms and regulators implicated in the generation of the
immunosuppressive TME that characterizes pancreatic tumorigenic process and to reverse it through
pharmacological and microbial interventions. Our laboratory found that IL-17-secreting immune cells play an
important role in promoting pancreatic tumorigenesis in genetically engineered mouse (GEMM) models of
pancreatic cancer. We now plan to characterize the mechanisms by which IL-17 promotes tumorigenesis by
genetically deleting the IL-17 receptor specifically from the pancreatic oncogenic epithelium using GEMM and
CRISPR/Cas9 (Aim 1). We also found that IL-17 neutralization decreases recruitment of myeloid cells, mostly
neutrophils, and induces CD8+T cells activation and in PDAC orthotopic model. Monoclonal antibodies against
IL-17 or neutrophils will be used to assess the mechanisms employed by IL-17 supporting an
immunosuppressive TME (Aim 2). Finally, we have recently found that fecal microbial transplants can modulate
tumors systemically. In particular, human PDAC-associated gut bacteria is capable of increasing IL-17 levels in
circulation, which may affect distant tumors like pancreatic cancer. We now plan to definitively address the role
gut bacteria in promoting Th17 differentiation and its systemic implications by performing human-into-mice fecal
microbial transplants (Aim 3). Achieving our goals will not only help us better understand immunological as well
as microbial mechanisms implicated in pancreatic tumorigenesis, but will also result in practical novel
interventions with either monoclonal antibodies, narrow spectrum antibiotics or microbial transplants that would
have a direct impact in preventing and/or treating this deadly disease.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><Address><Affect><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Apoptosis><Apoptosis Pathway><B7 family member, H4><B7 superfamily member 1><B7-H4><B7H4><B7S1><B7X><Blocking Antibodies><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Cause><Cancer Etiology><Cancers><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Circulation><Clinic><Clinical Treatment Moab><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Colon Cancer><Colon Carcinoma><Complex><Data><Development><Disease><Disorder><Distant><Environment><Epithelial Cells><Epithelium><Event><FDA approved><FLJ22418><GEM model><GEMM model><Generations><Genetic><Genetically Engineered Mouse><Goals><Grant><Host Defense><Human><Immune><Immune infiltrates><Immune mediated therapy><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Incidence><Inflammatory><Interleukin Receptor><Interleukins><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Lab Findings><Laboratory Finding><Learning><Lesion><Link><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Marrow Neutrophil><Mediating><Mediator><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modality><Modeling><Modern Man><Monoclonal Antibodies><Murine><Mus><Myeloid Cells><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Oncogenesis><Oncogenic><Outcome><PanIN><Pancreas><Pancreas Adenocarcinoma><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Adenocarcinoma><Pancreatic Cancer><Pancreatic Duct Dysplasia><Pancreatic Ductal Dysplasia><Pancreatic Intraepithelial Neoplasia><Pancreatic Tumor><Patients><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preclinical Testing><Preventive><Process><Programmed Cell Death><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Reporting><Resistance><Risk Factors><Role><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Source><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Translating><Transplantation><V-set domain containing T cell activation inhibitor 1><VTCN1><VTCN1 gene><activate T cells><bacteria in the gut><biological signal transduction><cancer in the colon><cancer microenvironment><check point blockade><checkpoint blockade><chronic pancreatitis><cytokine><design><designing><developmental><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><genetically engineered mouse model><genetically engineered murine model><gut bacteria><gut microbes><gut microbial species><host response><immune cell infiltrate><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><in vivo><inhibitor><innovate><innovation><innovative><interventional strategy><intestinal microbes><lung cancer><mAbs><malignancy><microbial><monoclonal Abs><mortality><neoplasm/cancer><neutrophil><novel><pancreas duct dysplasia><pancreas ductal dysplasia><pancreatic cancer model><pancreatic carcinogenesis><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic oncogenesis><pancreatic tumor model><pancreatic tumorigenesis><pathogen><pharmacologic><pre-clinical testing><precancer><precancerous><premalignant><prevent><preventing><receptor><recruit><recurrent pancreatitis><resistance to therapy><resistant><resistant to therapy><response><social role><therapeutic resistance><therapy resistant><thymus derived lymphocyte><tool><transcriptome sequencing><transcriptomic sequencing><transplant><treatment resistance><tumor><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><tumorigenesis><tumorigenic>