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Determinants of response to cancer immunotherapy

癌症免疫治疗反应的决定因素

基本信息

批准号：
10299968
负责人：
Lawrence Fong
金额：
$ 81.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2021-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299968
关键词：
Advanced Malignant Neoplasm Antigens Antitumor Response Basic Science Blood CD4 Positive T Lymphocytes Cancer Patient Cells Clinical Clinical Trials Clone Cells Combination immunotherapy Drug Targeting Future Genomics Goals Immune Immune checkpoint inhibitor Immunosuppression Immunotherapy Knock-out Maps Mediating Modality Neoadjuvant Therapy Operative Surgical Procedures Pathway interactions Patients Positioning Attribute Proteomics Research Resected Resistance T cell receptor repertoire sequencing T-Lymphocyte Therapeutic Translating Translational Research anti-tumor immune response base bench to bedside cancer immunotherapy cancer therapy cell type combinatorial cytotoxic design experience functional plasticity high dimensionality immune checkpoint blockade insight interest mouse model multidisciplinary neoplastic cell novel response single-cell RNA sequencing success tumor

项目摘要

PROJECT SUMMARY/ABSTRACT While immunotherapy is transforming cancer treatment, the majority of patients do not achieve durable responses. We have been studying response and resistance to different immune checkpoint inhibitors and are now poised to propose mechanistic studies aimed at providing an understanding of the immune states and pathways that mediate or inhibit response to immune checkpoint blockade. Using high-dimensional unbiased single-cell RNA-seq (scRNAseq), we can identify both canonical and non-canonical immune effectors that can mediate anti-tumor responses. We believe that non-canonical effectors such as cytotoxic CD4 T cells, which we have recently described, are not effectively triggered by our current treatments. Using the same single-cell approaches, we can identify both known and novel cell types in cancer patients that can mediate immune suppression. In our first objective, we will determine whether combination immunotherapies that include drug(s) targeting specific immunosuppressive cells can enhance the function of these cytotoxic CD4+ T cells. By leveraging neoadjuvant clinical trials where patients receive immunotherapy prior to surgery, we will use single cell genomics and proteomics to define whether these combinations can 1) target the desired immunosuppressive mechanisms, and 2) enhance canonical and/or non-canonical effectors within the resected tumors. We will also use this approach to determine whether we can map these specific cell states into the circulating compartment. The second objective is based on a longstanding interest in our group to define the dynamics of antigen-specific responses. Using single-cell T cell receptor sequencing, we can identify expanded T cell clones as well as follow their localization. In addition to understanding how immunotherapy combinations induce and modulate specific T cell clonotypes within the tumor, we can determine how immunotherapies can induce functional plasticity to desired or undesired states. The third objective builds on our 20 year experience using mouse models to dissect mechanisms underlying response or resistance to immunotherapy. We will determine the functional significance of non-canonical immune effectors using depletion and knock-out strategies. We will also determine how combination immunotherapies can elicit both effective or ineffective anti- tumor immune responses, thereby guiding the design of future clinical trials. In conclusion, our proposal is based on hypothesis-driven bench-to-bedside and bedside-to-bench mechanistic studies with the goal of advancing cancer immunotherapy. With our deep expertise in this field, experience leading multi-disciplinary teams focused on translational research, and a rich network of basic science and clinical collaborators; we are uniquely positioned to succeed in the research plan outlined in this proposal.

项目总结/文摘