Dissecting the source and mechanisms of IL-17-mediated modulation of pancreatic tumorigenesis

剖析 IL-17 介导的胰腺肿瘤发生调节的来源和机制

• 批准号: 10667495
• 负责人: Florencia McAllister
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667495
• 关键词: 16S ribosomal RNA sequencing; Address; Affect; Antibiotics; Apoptosis; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cancer Etiology; Cells; Chronic; Circulation; Clinic; Colon Carcinoma; Complex; Data; Development; Disease; Distant; Environment; Epithelial Cells; Epithelium; Event; FDA approved; Generations; Genetic; Genetically Engineered Mouse; Goals; Grant; Host Defense; Human; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Immunotherapy; Incidence; Inflammatory; Interleukin Receptor; Interleukins; Intervention; Knowledge; Laboratory Finding; Learning; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Mediator; Methods; Modality; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Neutrophil Infiltration; Oncogenic; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Play; Preclinical Testing; Preventive; Process; Regulation; Reporting; Resistance; Risk Factors; Role; Serum; Signal Transduction; Source; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Translating; Transplantation; VTCN1 gene; chronic pancreatitis; cytokine; design; fecal transplantation; gut bacteria; gut microbes; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; immunoregulation; in vivo; inhibitor; innovation; microbial; mortality; neutrophil; novel; pancreatic cancer model; pancreatic neoplasm; pancreatic tumorigenesis; pathogen; pharmacologic; premalignant; prevent; receptor; recruit; response; therapy resistant; tool; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenesis; tumorigenic

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.

摘要

项目成果

Too much water drowned the miller: Akkermansia determines immunotherapy responses.

• DOI: 10.1016/j.xcrm.2022.100642
• 发表时间: 2022-05-17
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Li, Le;McAllister, Florencia
• 通讯作者: McAllister, Florencia

Genetics of Pancreatic Neuroendocrine Tumors.

• DOI: 10.1016/j.hoc.2022.07.005
• 发表时间: 2022-09
• 期刊: Hematology/oncology clinics of North America
• 作者: Chirayu Mohindroo;F. McAllister;A. De Jesus-Acosta

Mouse Models to Study Secondary Cancer Prevention.

研究二级癌症预防的小鼠模型。

• DOI: 10.1007/978-1-0716-2014-4_16
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Li,Le;Chandra,Vidhi;McAllister,Florencia;Zhang,Yu
• 通讯作者: Zhang,Yu

Bacterial and fungal characterization of pancreatic adenocarcinoma from Endoscopic Ultrasound-guided biopsies.

• DOI: 10.3389/fimmu.2023.1268376
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Wright, Robin D.;Bartelli, Thais F.;Baydogan, Seyda;White, James Robert;Kim, Michael P.;Bhutani, Manoop S.;Mcallister, Florencia
• 通讯作者: Mcallister, Florencia

Therapeutic potential of microbial modulation in pancreatic cancer.

• DOI: 10.1136/gutjnl-2019-319807
• 发表时间: 2021-04-27
• 期刊: Gut
• 影响因子: 24.5
• 作者: Chandra V;McAllister F
• 通讯作者: McAllister F