Dissecting mechanisms of immunotherapy resistance in melanoma patients

剖析黑色素瘤患者免疫治疗耐药的机制

基本信息

批准号：
10231195
负责人：
Benjamin Izar
金额：
$ 12.46万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2017-09-14 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231195
关键词：
Advisory Committees Angiogenesis Pathway Biological Biological Response Modifiers Biopsy CRISPR/Cas technology CTLA4 gene Cancer Biology Cancer Patient Caring Cell Communication Cell Line Cells Clinical Clinical Trials Coculture Techniques Collaborations Computer Analysis Dana-Farber Cancer Institute Development Disease Disease remission Drug resistance Enrollment Environment Evaluation Formalin Genetic Genetic Screening Genetic Transcription Goals Image Immune Immune checkpoint inhibitor Immunobiology Immunooncology Immunotherapy KDR gene Knock-out Ligands Link Malignant Neoplasms Mediating Melanoma Cell Mentors Mentorship Metastatic Melanoma Methods Modeling Molecular Molecular Analysis Nivolumab PD-1/PD-L1 Paraffin Embedding Patients Pharmacology Phosphotransferases Physicians Physiological Procedures Protein Analysis Proteins Research Research Personnel Resistance Role Sampling Scientist Signal Transduction Site Skin Cancer Specimen T-Lymphocyte Technology Testing Therapeutic Tissues Training Translating Tumor-Infiltrating Lymphocytes Validation Vascular Endothelial Growth Factors Work angiogenesis anti-PD1 therapy bevacizumab biomarker discovery cancer care cancer pharmacology checkpoint therapy clinical application clinically relevant cohort gain of function genome-wide improved ipilimumab medical schools meetings melanoma multimodality multiplexed imaging novel drug combination novel therapeutics pembrolizumab predicting response prospective protein expression receptor resistance mechanism response single-cell RNA sequencing spatiotemporal technological innovation therapy development therapy resistant transcriptome transcriptome sequencing treatment strategy tumor tumor heterogeneity

项目摘要

Project Summary / Abstract Metastatic melanoma is the most aggressive form of skin cancer and a devastating disease. The development of immune checkpoint inhibitors (ICI) represents a major therapeutic improvement in melanoma care, inducing durable responses in a portion of patients. However, the majority of patients has intrinsic or acquired resistance to ICI and derives no benefit from these therapies. The molecular underpinnings of ICI-resistance are poorly understood. The overarching goal of this proposal is to determine mechanisms of ICI-resistance in melanoma using several experimental and technological innovations. We performed single-cell RNA- sequencing (sc-RNA-seq) and multiplexed imaging of ICI-resistant melanoma tumors, and a genome-scale gain-of-function screen in patient-derived melanoma cell lines and their corresponding tumor infiltrating lymphocytes (TILs). Our sc-RNA-seq analysis revealed a strong association between melanoma cell- autonomous expression of angiogenesis pathways with ICI-resistance. In line with this finding, our functional genetic screen identified KDR (also known as VEGFR2) as top hit of putative mediators of immune escape. KDR is a major receptor for vascular endothelial growth factor (VEGF) and induces the expression of angiogenesis pathways that were identified by sc-RNA-seq. Multiplexed imaging confirmed protein expression of KDR at the invasive tumor front, a key site of tumor-immune interactions in melanoma that predicts response and resistance to ICI. Together, these preliminary results highlight the putative role of KDR and downstream angiogenesis pathway expression in ICI-resistance. This proposal builds on these findings with the specific focus to: 1) dissect the mechanisms of KDR-mediated immune escape, 2) validate transcriptional and protein expression of KDR and its downstream angiogenesis pathways in patients undergoing serial biopsies while receiving ICI therapy, and 3) functionally validate mechanisms of ICI-resistance in isogenic patient-derived cell lines. Results of these studies have the potential to guide novel drug combination strategies that could be rapidly translated into clinical application. Dr. Benjamin Izar is mentored by Dr. Kai Wucherpfennig, a physician-scientist and expert in immuno-oncology, and Dr. Aviv Regev, a pioneer in sc- RNA-seq and computational analyses. Dr. Izar has a committed advisory committee comprised of Drs. Stephen Hodi, Keith Flaherty and Peter Sorger, who will provide additional mentorship and collaboration in immuno-oncology, cancer biology and pharmacology. Dr. Izar has developed a 5-year training plan with a detailed outline of activities that will facilitate his development to an independent investigator. Dr. Izar will leverage an exceptional research environment at Dana-Farber Cancer Institute, Harvard Medical School and the Broad, and a richness of scientific meetings, professional development seminars and didactic coursework.

项目摘要 /摘要转移性黑色素瘤是皮肤癌和毁灭性疾病最具侵略性的形式。发展免疫检查点抑制剂（ICI）代表了黑色素瘤护理的主要治疗方法一部分患者的耐用反应。但是，大多数患者具有内在或获得的对ICI的抵抗力并没有从这些疗法中获得任何好处。 ICI抗性的分子基础知之甚少。该提案的总体目标是确定ICI抗性的机制黑色素瘤使用几项实验和技术创新。我们进行了单细胞RNA- ICI耐药性黑色素瘤肿瘤的测序（SC-RNA-SEQ）和多重成像和基因组规模患者衍生的黑色素瘤细胞系及其相应肿瘤浸润的功能屏幕淋巴细胞（TILS）。我们的SC-RNA-seq分析表明，黑色素瘤细胞之间存在很强的关联具有ICI抗性的血管生成途径的自主表达。根据这一发现，我们的功能遗传筛查鉴定出KDR（也称为VEGFR2）是免疫逃脱的假定介体的最高命中。 KDR是血管内皮生长因子（VEGF）的主要受体，并诱导表达通过SC-RNA-Seq鉴定的血管生成途径。多重成像确认的蛋白质表达在侵入性肿瘤前部的KDR，这是黑色素瘤中肿瘤免疫相互作用的关键部位对ICI的反应和抵抗力。这些初步结果共同凸显了KDR和 ICI抗性中的下游血管生成途径。该提议以这些发现为基础特定的重点：1）剖析KDR介导的免疫逃逸的机制，2）验证转录在接受系列的患者中，KDR及其下游血管生成途径的蛋白质表达活检在接受ICI治疗时，3）在功能上验证ICI抗性机制患者衍生的细胞系。这些研究的结果有可能引导新型药物组合可以快速转化为临床应用的策略。本杰明·伊扎尔（Benjamin Izar）博士由凯博士指导 Wucherpfennig，医师科学家和免疫肿瘤学专家，以及SC-的先驱Aviv Regev博士 RNA-seq和计算分析。伊扎尔博士由Drs组成的承诺咨询委员会。 Stephen Hodi，Keith Flaherty和Peter Sorger，他们将在免疫肿瘤，癌症生物学和药理学。伊扎尔博士已经制定了一项为期5年的培训计划详细的活动概述将促进他向独立调查员的发展。伊扎尔·威尔博士利用达纳 - 法伯癌症研究所，哈佛医学院和广泛的科学会议，专业发展研讨会和教学课程。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alpha-fetoprotein (AFP) as tumor marker in a patient with urothelial cancer with exceptional response to anti-PD-1 therapy and an escape lesion mimic.

DOI：
10.1186/s40425-018-0394-y
发表时间：
2018-09-12
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
Melms JC;Thummalapalli R;Shaw K;Ye H;Tsai L;Bhatt RS;Izar B
通讯作者：
Izar B

Rapid evolution of acute kidney injury after initial infusion of pembrolizumab in a melanoma patient concurrently treated with RAF/MEK inhibitors.

DOI：
10.1097/cmr.0000000000000646
发表时间：
2020-04
期刊：
Melanoma research
影响因子：
2.2
作者：
Thummalapalli R;Melms JC;Mier J;Izar B
通讯作者：
Izar B

Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade.

DOI：
10.1002/cam4.3789
发表时间：
2021-04
期刊：
Cancer medicine
影响因子：
4
作者：
Buchbinder EI;Weirather JL;Manos M;Quattrochi BJ;Sholl LM;Brennick RC;Bowling P;Bailey N;Magarace L;Ott PA;Haq R;Izar B;Giobbie-Hurder A;Hodi FS
通讯作者：
Hodi FS