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Proteomic determinants of response to checkpoint blockade in malignant pleuralmesothelioma

恶性胸膜间皮瘤检查点阻断反应的蛋白质组决定因素

基本信息

批准号：
10545173
负责人：
Bryan Michael Burt
金额：
$ 49.59万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545173
关键词：
Acceleration Antigen Targeting Architecture Atlases Bioinformatics Biological Markers Biology Caring Cells Clinical Clinical Data Cytometry Data Disease Elements Formalin Frequencies Human Image Immune Immune checkpoint inhibitor Immunohistochemistry Immunologics Life Life Extension Lung MHC antigen Malignant - descriptor Malignant Neoplasms Malignant Pleural Mesothelioma Mass Spectrum Analysis Measures Nivolumab Operative Surgical Procedures PD-1 blockade Paraffin Embedding Patient Care Patients Peptides Pharmaceutical Preparations Phenotype Pleura Production Prospective cohort Protein Analysis Proteins Proteomics Radiation therapy Resistance Sampling Signal Transduction Specimen Structure T cell response T-Lymphocyte Techniques Testing Time Tissues Toxic effect Translating Triage Tumor Burden Validation abstracting anti-PD-1 antigen detection bioinformatics pipeline cancer therapy cell type chemotherapy clinical application clinical biomarkers clinical translation cohort cost cytokine design effective therapy exome sequencing high dimensionality human leukocyte antigen testing immune checkpoint blockade immunogenicity improved in silico indexing innovation malignant pleura tumor neoantigens novel novel marker predicting response predictive marker programmed cell death ligand 1 prospective prospective test responders and non-responders response side effect single cell analysis standard of care time use traditional therapy transcriptome sequencing tumor tumor heterogeneity tumor-immune system interactions

项目摘要

PROJECT SUMMARY / ABSTRACT Malignant pleural mesothelioma (MPM) is a fatal cancer of the lining of the lungs that has defeated standard therapies for decades. Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, and tumor- specific neoantigens are critical components of the vigorous anti-tumor T cell responses possible from these agents. Emerging clinical data show that ICIs result in meaningful extension of life in half of patients with MPM but are associated with immune-related side effects. There is no reliable biomarker for identifying MPM patients who will respond to ICIs. Such a test would avoid unnecessary toxicity, triage non-responders to potentially more effective treatment, and could even extend long-term survival. Our preliminary data show that MPM tumors from patients that respond favorably to ICIs are rich in 1) distinct cellular and tissue architectural features of MPM's unique immune contexture, and 2) abundant tumor neoantigens that are detected at the peptide level and expressed concomitantly with the specific HLA proteins that are required for their presentation to T cells. Our central hypothesis is that response to PD-1 blockade in MPM can be predicted by a clinically-applicable biomarker of its immunologic organization and requires neoantigen:MHC concordance. In Aim 1, we will apply the high dimensional platforms of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry (IMC) to dissect the cellular networks and immuno-architectural features of MPM that govern response to nivolumab. Based on these features, we derived a novel score that predicts response to nivolumab in MPM and we have developed an innovative bioinformatics platform to abstract this score from standard formalin-fixed paraffin- embedded (FFPE) clinical tissue sections. In Aim 1, we will optimize and prospectively validate this score in patients with MPM. In Aim 2, we will perform mass spectrometry (MS) on HLA-typed tumors to investigate neoantigen biology and challenge the prevailing biomarker of neoantigen burden that is used clinically to predict response to ICIs in other tumors, but with low accuracy. This biomarker has relied exclusively on neoantigens predicted in silico and does not directly measure neoantigens in tumors. We found that high quantities of MHC- I and MHC-II neoantigens detected by MS in MPM tumors (termed neoantigen abundance) correlated with sensitivity to nivolumab. More interestingly, we found that the MPM tumors most likely to respond had high peptide level expression of neoantigens concordant with high protein level expression of the specific HLA proteins required for their presentation (termed neoantigen:MHC concordance). These novel metrics will be tested prospectively in Aim 2 where we will also validate the immunogenicity of MS-detected neoantigens and determine the phenotype of neoantigen-reactive T cells. Our results will define core elements of the immunoproteomic structure of MPM and result in the clinical translation of innovative biomarkers expected to directly improve the care of MPM patients. More broadly, completion of this project will advance our understanding of neoantigen biology and of mechanisms of response and resistance to ICIs in human cancer.

项目摘要/摘要