Autophagy mediated immune stimulation by reovirus in KRAS mutated colorectal cancer

KRAS 突变结直肠癌中呼肠孤病毒自噬介导的免疫刺激

• 批准号: 10359958
• 负责人: Radhashree Maitra
• 金额: $ 43.4万
• 依托单位: YESHIVA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-14 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359958
• 关键词: Address; Adopted; Area; Autophagocytosis; Autophagosome; Biogenesis; Biological Assay; Biomedical Research; Carbamazepine; Cell Survival; Cells; Characteristics; Chloroquine; Clinic; Clinical; Colorectal Cancer; Colorectal Neoplasms; Development; Disease; Double-Stranded RNA; Environment; Enzyme-Linked Immunosorbent Assay; Etiology; Event; FDA approved; Flow Cytometry; Genome; Homing; Hour; Immune; Immune checkpoint inhibitor; Immunization; Immunofluorescence Immunologic; Immunotherapy; Interferons; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-12; Interleukin-6; Interleukins; Intervention; KRAS oncogenesis; KRAS2 gene; Knowledge; Malignant Neoplasms; Mediating; Medical; Microscopy; Molecular; Mus; Mutate; Oncolytic; Ownership; Pathway interactions; Patients; Pattern; Phagolysosome; Plasma; Positron-Emission Tomography; Process; Property; Proteins; Recommendation; Recycling; Reovirus; Research; Research Personnel; Research Support; Role; Science; Stains; Students; T-Lymphocyte; TNF gene; Tamoxifen; Therapeutic; Time; Transforming Growth Factor beta; Transgenic Organisms; Translating; Transmission Electron Microscopy; Treatment Efficacy; Treatment Protocols; Tumor Tissue; Western Blotting; Work; anti-PD1 antibodies; cancer type; checkpoint therapy; cohort; colon cancer cell line; colon cancer patients; cytokine; experimental study; fluorodeoxyglucose; immune activation; improved; inhibitor; insight; mouse model; mutant; neoplastic cell; novel; oncolysis; post intervention; programmed cell death protein 1; programs; response; success; targeted treatment; transmission process; treatment strategy; tumor; tumor microenvironment; undergraduate student

Project Summary The impressive success of cancer immune therapy reached its limitations and failed in its efficacy with immune deserted KRAS mutated tumors that constitute 45% of colorectal cancers. These patients have fewer treatment options necessitating the development of effective alternate therapy. Of late reovirus, with a double- stranded RNA genome, showed therapeutic efficacy in an oncogenic KRAS transformed colorectal tumors. Although previously studied for its oncolytic properties reovirus is being increasingly appreciated for its immune stimulation properties. However, its participation in immune stimulation, precisely utilizing two intimately related immune and autophagic modulatory pathways, remains largely unexplored. Preliminary results indicate that reovirus preferentially exploits the immune deserted mutant KRAS tumor microenvironment to successfully support its propagation in conjunction with destruction of the tumor cells. Furthermore, reovirus induces autophagy in KRAS mutated microenvironment. Knowledge gaps: It is crucial to understand the mechanism adopted by reovirus to facilitate the immune enrichment of mutant KRAS driven immune deserted microenvironment in colorectal cancer. The contribution of autophagic pathway in accentuating the process is unclear. Understanding the control mechanism between the autophagy and immune pathways is critical. Project hypothesis: The dual mode of action exerted by reovirus can be successfully translated to the clinic by augmenting the induction of the autophagy pathway. We propose to study the pattern of reovirus mediated induction of the autophagic machinery and determine how the molecular event is translated in improving the immune stimulation characteristics in KRAS mutated colorectal Cancer. In this context we will make use of KRAS mutant and wildtype colorectal cancer cell lines and our newly developed KPC:APC (tamoxifen- inducible KRAS-mutated colorectal cancer) mouse models along with the well-established syngeneic mouse model of colorectal cancer to mechanistically explore the process of crosstalk between the two pathways. Results will improve the understanding of the dynamics of KRAS mutated immune deserted cold tumors in facilitating reovirus to act as an immune stimulator Impact: This project will have dual impact of providing an enriched biomedical science related research environment to the aspiring undergraduate students as well as to directly address the clinical gap faced by the KRAS mutated colorectal cancer patients. Understanding the mechanism of cross talk between the autophagy and immune pathways followed by research supported recommendation of therapeutic induction of autophagy to improve immune therapy responsiveness of KRAS mutated colorectal cancer will be of paradigm clinical implications. In this pursuit we will AIM1: Demonstrate crosstalk between autophagy and immune pathways in reovirus treated KRAS mutant and wildtype colorectal cancer cell lines. AIM2: Examine if autophagy induction promotes reovirus mediated immune stimulation in KRAS mutated cold colorectal tumors in transgenic and syngeneic mouse models.

项目总结