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(PQ3) Disruption of immune surveillance by aneuploidy and aberrant MHCII expression

(PQ3) 非整倍体和异常 MHCII 表达破坏免疫监视

基本信息

批准号：
10223222
负责人：
Hannah Kathryn Carter
金额：
$ 31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223222
关键词：
Address Aftercare Aneuploidy Antigens B-Lymphocytes Cancer Center Cancer Control Cancer Patient Cells Cellular biology Characteristics Chemicals Chromosome abnormality Clinical Clonality Complex Consensus Data Dendritic Cells Failure Funding Opportunities Genomics Heterogeneity Human Immune Immune response Immune system Immunity Immunocompetent Immunologic Surveillance Immunologics Immunotherapy Impairment In Vitro Individual Inflammatory Intervention Light Link Major Histocompatibility Complex Malignant Neoplasms Measures Mediating Molecular Chaperones Mus Myeloid Cells Natural Killer Cells Outcome Patients Pharmacology Phenotype Play Population Proxy Publishing Regulation Research Role Sampling Stress T-Lymphocyte Testing The Cancer Genome Atlas Tissue Banks Tumor Immunity Tumor-infiltrating immune cells Validation anti-cancer arm base cancer cell cancer genomics clinical predictors design experimental study high risk immune checkpoint blockade immune function immunotherapy trials in vivo lens macrophage patient oriented patient population patient stratification peripheral blood predictive signature prognostic proteotoxicity response survival prediction tauroursodeoxycholic acid transcriptome sequencing tumor tumor microenvironment

项目摘要

This new R01 application is submitted in response to Funding Opportunity RFA-CA-15-008 “Research Answers to NCI's Provocative Questions”. The hypothesis to be tested is in response to PQ3. We hypothesize that the benefit afforded by immune surveillance to the individual and populations of cancer patients may depend on the levels of aneuploidy and expression of the Major Histocompatibility Complex (MHC) complex Class II (MHCII) in the tumor. We further predict that a population of individuals defined by tumors with high aneuploidy and low MHCII expression is at higher risk of progression and poor outcome, and unresponsiveness to immunotherapy by regulating the size and composition of intra-tumor immune infiltrates. Within this new paradigm, we also propose to investigate the possible causative mechanism of aneuploidy- induced proteotoxic stress. The study will be a combination of genomic analyses and immunological interrogation in UCSD Moores Cancer Center patients, and will ultimately seek validation in through TCGA data as well as data from immunotherapy trials. We propose four Aims. (1) To validate aneuploidy/MHC II as predictors of progression and clinical outcome. TCGA data will be interrogated to relate an association between aneuploidy and levels of MHCII expression to overall survival. and response in immunotherapy (ICPi) trials. (2) To measure markers of natural immune response in cancer patients grouped according to aneuploidy/MHC II status. We will study the size and clonality of tumor-infiltrating T cells by profiling TCR reactive with TERT, an antigen expressed by cancer cells at every stage of differentiation, as a proxy of the autochthonous anti-cancer response. By comparing tumor-infiltrating T cells to circulating T cells, we expect to determine if (a) tumor the aneuploidy/MHCII signature predicts T cell infiltration, and (b) lower immune T cell infiltration displays high TCR heterogeneity. (3) To determine whether aneuploidy/MHCII status interferes with response to ICPi therapy. We will determine if high aneuploidy/low MHCII expression impairs immune reactivation after ICPi therapy, and use immunoscore from responder and nonresponder patients. (4) To determine whether proteotoxic stress is the mechanism by which aneuploidy interferes with immune response. Because aneuploidy induces proteotoxic stress, the ensuing UPR provides a mechanistic link between cancer cell biology and immune surveillance. In vitro and in vivo experiments using cells with pharmacologically-induced aneuploidy will be used to determine the extent to which UPR cell nonautonomous effects may account for a disruption of local immunity, i.e., number and characteristics of tumor infiltrating myeloid cells. We believe that an analysis at the interface between cancer genomic and immune surveillance may reveal general rules for immune-mediated control of cancer. This may help stratify patients and their clinical trajectory, and predict clinical responses to immunotherapy more accurately. !

这份新的R01申请是为了响应资助机会RFA-CA-15-008“研究”而提交的

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In silico analysis suggests less effective MHC-II presentation of SARS-CoV-2 RBM peptides: Implication for neutralizing antibody responses.

DOI：
10.1371/journal.pone.0246731
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Castro A;Ozturk K;Zanetti M;Carter H
通讯作者：
Carter H

Ubi Maior Minor Cessat.

乌比·马约尔·小塞萨特。

DOI：
10.1615/critrevimmunol.2020034859
发表时间：
2020
期刊：
Critical reviews in immunology
影响因子：
1.3
作者：
Zanetti,Maurizio
通讯作者：
Zanetti,Maurizio

Neoantigen Controversies.

DOI：
10.1146/annurev-biodatasci-092820-112713
发表时间：
2021-07-20
期刊：
Annual review of biomedical data science
影响因子：
0
作者：
通讯作者：

The unfolded protein response links tumor aneuploidy to local immune dysregulation.

未折叠的蛋白质反应将肿瘤非整倍性与局部免疫失调联系起来。

DOI：
10.15252/embr.202152509
发表时间：
2021-12-06
期刊：
EMBO reports
影响因子：
7.7
作者：
Xian S;Dosset M;Almanza G;Searles S;Sahani P;Waller TC;Jepsen K;Carter H;Zanetti M
通讯作者：
Zanetti M

Transcriptional analysis links B cells and TERT expression to favorable prognosis in head and neck cancer.