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Investigating splicing-derived antigens in the context of Rbm10-mutant lung adenocarcinoma

研究 Rbm10 突变肺腺癌中的剪接衍生抗原

基本信息

批准号：
10606839
负责人：
Nicolas Mathey-Andrews
金额：
$ 5.27万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606839
关键词：
Adaptive Immune System Adenocarcinoma Advanced Malignant Neoplasm Animals Antibodies Antigen Presentation Antigens Binding Bioinformatics Biological Markers CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cancer Etiology Cells Cessation of life Common Neoplasm Development Dose Epitopes Event Exhibits Genes Genetically Engineered Mouse Genome engineering Genotype Goals Growth Histologic Human Immune Immune response Immune system Immunocompetent Immunoprecipitation Immunotherapy Infiltration Knock-out Lung Lung Adenocarcinoma Lung Neoplasms Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Methods Modeling Mutation Patients Pattern Peptide/MHC Complex Peptides Predisposition Productivity Protein Fragment Proteins Publishing RNA Splicing Recurrence Role Somatic Mutation Suppressor Mutations T cell response T-Cell Depletion T-Lymphocyte Testing Transcript Translating Translations Tumor Antigens Tumor Burden Tumor Immunity Work adaptive immune response anti-PD-1 anti-tumor immune response antigen-specific T cells cancer cell cancer genome cancer immunotherapy clinical predictors cohort driver mutation immune cell infiltrate immune checkpoint blockade immunogenic immunogenicity in vivo Model innovation loss of function mutation mRNA sequencing mouse model mutant neoantigens neoplastic cell novel novel therapeutics patient stratification patient subsets predicting response programmed cell death ligand 1 research study response restraint standard of care transcriptome sequencing tumor

项目摘要

Project summary: The adaptive immune system can specifically recognize and kill cancer cells. Therapies that reinvigorate tumor-specific CD8 T cells cure a subset of patients with lung cancer, prompting their FDA approval and use as standard of care. Tumor-reactive T cells recognize cancer cell antigens -- displayed fragments of proteins that are unique to tumor cells. To date, study of anti-tumor immunity has primarily focused on antigens derived from somatic mutations in the cancer genome, which are insufficient to fully explain the anti-tumor immune response. Moreover, mutation-derived neoantigens are generally unique to each tumor, and targeting them might require bespoke treatments for each patient. The long-term goal of this proposal is to expand the paradigm of cancer-specific antigens. Recent work has uncovered a novel class of cancer-restricted antigens produced by abnormal splicing events. While several cancers harbor recurrent driver mutations in splicing factors, few studies have explored the relationship between dysregulated splicing and tumor immunogenicity. Notably, ~10% of lung adenocarcinomas feature loss-of-function mutations in RBM10, a critical splicing factor. This work will examine splicing-derived antigens in Rbm10-deficient tumors. The central hypothesis is that Rbm10 deficiency will generate aberrantly spliced transcripts, which will elicit an adaptive immune response if translated and presented as novel antigens by tumor cells. This hypothesis will be tested in a well- characterized murine model of lung adenocarcinoma by pursuing two specific aims. In Aim 1, mRNA sequencing will be performed to characterize aberrant splicing events that occur in the context of Rbm10 deficiency. Mass spectrometry will be used to validate that aberrantly spliced RNAs produce antigens presented to the immune systems. In Aim 2, CRISPR/Cas9 will be used to introduce Rbm10 mutations in an immunocompetent, autochthonous murine model. Histologic and flow cytometric analyses will be performed on infiltrating lymphocytes in Rbm10-deficient and proficient tumors to assess endogenous anti-tumor immunity. This research study is innovative in that it proposes to empirically test the role of splicing-derived antigens in anti-tumor immunity using genome engineering in autochthonous mouse models. It is significant because it may identify new, tumor-restricted antigens that are targetable by cancer immunotherapies. While T-cell targeted immunotherapies provide durable cures for patients with advanced cancer, prior studies emphasize a limited set of cancer-specific T cell antigens. The ultimate objective of this work is to uncover novel mechanisms to potentiate immune recognition of cancer cells, leading to the development of new therapies for lung cancer.

项目总结: