MHC Class II Antigen Presentation In Melanoma: Impact on Immune Recognition

黑色素瘤中 MHC II 类抗原的呈现：对免疫识别的影响

基本信息

批准号：
10674177
负责人：
KAREN TARASZKA HASTINGS
金额：
--
依托单位：
PHOENIX VA HEALTH CARE SYSTEM
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：
2021-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674177
关键词：
Address Advanced Malignant Neoplasm Affinity Antigen Presentation Antigens Arizona Award Biological Assay Biomimetics CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene Cancer Vaccines Cells Collaborations Complex Computer Models Computing Methodologies Cytoplasmic Tail Cytotoxic T-Lymphocytes Data Set Epitopes Hispanic-serving Institution Histocompatibility Antigens Class II Human Immune Immunotherapeutic agent Immunotherapy Induced Mutation Knowledge Legal patent Lymphocyte-Specific p56LCK Tyrosine Protein Kinase MHC Class II Genes Membrane Methods Missense Mutation Modeling Mus Mutate Peptide Library Peptide/MHC Complex Peptides Proliferating Regulation Regulatory T-Lymphocyte Research Research Personnel Risk Factors Signal Transduction T cell response T cell therapy T-Cell Depletion T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Technology Testing UV induced Universities Veterans anti-PD-1 antigen-specific T cells cancer care cancer cell cancer clinical trial cancer immunotherapy cancer therapy checkpoint inhibition chimeric antigen receptor chimeric antigen receptor T cells clinically relevant computerized tools driver mutation efficacy evaluation efficacy testing high throughput screening immunogenic immunogenicity improved melanoma mouse model neoantigens new technology novel strategies prevent receptor response src-Family Kinases technological innovation tumor tumor immunology

项目摘要

Regulation of tumor-specific CD4 T cell responses holds great promise for improving cancer immunotherapy with immune checkpoint inhibition, cancer vaccines, and adoptive T cell therapy. Effective response to immunotherapy requires T cell recognition of mutated peptide epitopes from cancer cells, called neoantigens. Effective response to immunotherapy requires neoantigens capable of stimulating both CD4 and CD8 T cells. Tumor-specific CD4 T cells recognize neoantigens presented by MHC class II. However, experimental or computational methods for identification of MHC class II neoantigens that are immunogenic (elicit a T cell response) have not been well-established. While tumor-specific CD4 T cell epitopes are necessary to generate effective anti-tumor T cell responses to immunotherapy, CD4 regulatory T (Treg) cells that develop within tumors suppress the proliferation and function of other T cells. Destroying CD4 Treg cells is a promising immunotherapeutic approach. However, the lack of a method to specifically target and destroy tumor-specific CD4 Treg cells prevents depletion of Treg cells from advancing further in clinical trials for cancer immunotherapy. Peptide-MHC tetramers can be used to identify tumor-specific T cells. However, peptide-MHC class II tetramers cannot be generated for many peptide antigens that are known to elicit T cell responses due to low affinity or stability of the peptide interaction with MHC class II. This proposal will advance the field of cancer immunology by addressing three gaps in knowledge: 1) inability to use tetramers to identify most tumor- specific CD4 T cells, 2) inability to target tumor-specific Treg cells for destruction, and 3) lack of experimental and computational tools to prioritize immunogenic MHC class II neoantigens. This proposal will utilize a new, patented technology of a biomimetic 5-module chimeric antigen receptor (5MCAR). The 5MCAR consists of the ectodomains of peptide-MHC class II fused to the transmembrane and cytoplasmic domains of the T cell receptor, which facilitates assembly with the CD3 signaling complex, and a surrogate coreceptor composed of CD80 fused to the Src kinase Lck. The 5MCAR is expressed on a cytotoxic T cell. Signaling through the 5MCAR allows identification and killing of CD4 T cells expressing a T cell receptor than recognizes the peptide-MHC class II of the 5MCAR. The central hypothesis is that 5MCAR will facilitate determination of immunogenic MHC class II melanoma neoantigens and effectively treat melanoma tumors by destruction of tumor-specific CD4 Treg cells. The aim of this proposal is to identify immunogenic MHC class II neoantigens and test the efficacy of depleting neoantigen-specific CD4 cells in treating melanoma, using a clinically relevant, immunogenic mouse melanoma model. A cell based assay with 5MCAR will be used in high throughput screening with a peptide library to identify the MHC class II neoantigens which elicit CD4 conventional T cell and regulatory T cell responses in melanoma tumors. The efficacy of tumor-specific 5MCAR T cells in treating established melanoma tumors through depletion of neoantigen-specific Treg cells alone and in combination with immune checkpoint inhibition with anti-PD-1 will be assessed. Using the comprehensive, unbiased dataset generated from testing the immunogenicity of all missense mutations, a computational model to predict immunogenic MHC class II neoantigens will be created and validated. The impact of this proposal is to 1) establish a collaboration with Dr. Kuhns at the University of Arizona, a Hispanic Serving Institution, 2) incorporate a new technological innovation to allow high throughput screening for identification of immunogenic MHC class II neoantigens, targeted destruction of tumor-specific CD4 Treg cells, and improved computational methods for prioritization of immunogenic MHC class II neoantigens, 3) increase the impact of the Merit award by addressing gaps in the current knowledge that prevent advancement of cancer immunotherapy and ultimately improve cancer care for Veterans, and 4) assist underrepresented investigators engage in VA Research.

肿瘤特异性 CD4 T 细胞反应的调节为改善癌症免疫治疗带来了巨大希望免疫检查点抑制、癌症疫苗和过继性 T 细胞疗法。有效应对免疫疗法需要 T 细胞识别癌细胞中的突变肽表位（称为新抗原）。对免疫疗法的有效反应需要能够刺激 CD4 和 CD8 T 细胞的新抗原。肿瘤特异性 CD4 T 细胞识别 MHC II 类呈递的新抗原。然而，实验性或用于鉴定具有免疫原性的 MHC II 类新抗原（引发 T 细胞）的计算方法反应）尚未得到完善。虽然肿瘤特异性 CD4 T 细胞表位对于产生免疫治疗产生有效的抗肿瘤 T 细胞反应，CD4 调节性 T (Treg) 细胞在体内发育肿瘤抑制其他 T 细胞的增殖和功能。破坏 CD4 Treg 细胞是一种有前途的方法免疫治疗方法。然而，缺乏特异性靶向和破坏肿瘤特异性的方法 CD4 Treg 细胞可防止 Treg 细胞耗竭在癌症临床试验中进一步进展免疫疗法。肽-MHC 四聚体可用于鉴定肿瘤特异性 T 细胞。然而，肽-MHC 许多已知能引发 T 细胞反应的肽抗原无法生成 II 类四聚体，因为肽与 MHC II 类相互作用的亲和力或稳定性较低。该提案将推动该领域的发展癌症免疫学通过解决三个知识差距：1）无法使用四聚体来识别大多数肿瘤特异性 CD4 T 细胞，2) 无法靶向肿瘤特异性 Treg 细胞进行破坏，3) 缺乏实验以及优先考虑免疫原性 MHC II 类新抗原的计算工具。该提案将利用一个新的、仿生5模块嵌合抗原受体（5MCAR）专利技术。 5MCAR 包括肽-MHC II 类胞外域与 T 细胞的跨膜域和胞质域融合受体，促进与 CD3 信号复合物的组装，以及由以下组成的替代辅助受体 CD80 与 Src 激酶 Lck 融合。 5MCAR 在细胞毒性 T 细胞上表达。通过 5MCAR 发送信号允许识别和杀死表达 T 细胞受体的 CD4 T 细胞，而不是识别肽-MHC 5MCAR II 类。中心假设是 5MCAR 将有助于确定免疫原性 MHC II 类黑色素瘤新抗原，通过破坏肿瘤特异性 CD4 有效治疗黑色素瘤 Treg 细胞。本提案的目的是鉴定免疫原性 MHC II 类新抗原并测试其功效使用临床相关的免疫原性细胞清除新抗原特异性 CD4 细胞来治疗黑色素瘤小鼠黑色素瘤模型。基于细胞的 5MCAR 检测将用于高通量筛选肽库，用于识别 MHC II 类新抗原，从而引发 CD4 常规 T 细胞和调节性 T 细胞黑色素瘤中的细胞反应。肿瘤特异性 5MCAR T 细胞的治疗功效已确定通过单独耗竭新抗原特异性 Treg 细胞以及与免疫相结合来治疗黑色素瘤将评估抗 PD-1 的检查点抑制作用。使用生成的全面、公正的数据集通过测试所有错义突变的免疫原性，预测免疫原性的计算模型 MHC II 类新抗原将被创建和验证。该提案的影响是 1) 建立与亚利桑那大学的 Kuhns 博士（西班牙裔服务机构）合作，2) 纳入了一项新的技术创新可实现高通量筛选，以鉴定免疫原性 MHC II 类新抗原、靶向破坏肿瘤特异性 CD4 Treg 细胞以及改进的计算方法优先考虑免疫原性 MHC II 类新抗原，3) 通过以下方式增加优异奖的影响解决当前知识中阻碍癌症免疫疗法进步的差距，并最终改善退伍军人的癌症护理，4) 协助代表性不足的研究人员参与 VA 研究。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NeoScore Integrates Characteristics of the Neoantigen:MHC Class I Interaction and Expression to Accurately Prioritize Immunogenic Neoantigens.

NeoScore 整合了新抗原：MHC I 类相互作用和表达的特征，以准确优先考虑免疫原性新抗原。

DOI：
发表时间：
2022-04-01
期刊：
影响因子：
0
作者：
Borden, Elizabeth S;Ghafoor, Suhail;Buetow, Kenneth H;LaFleur, Bonnie J;Wilson, Melissa A;Hastings, K Taraszka
通讯作者：
Hastings, K Taraszka

High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.

高 GILT 表达与接受免疫检查点抑制治疗的转移性黑色素瘤患者的生存率提高相关。

DOI：
发表时间：
2022-04-28
期刊：
影响因子：
5.2
作者：
Adams, Anngela C;Borden, Elizabeth S;Macy, Anne M;Thomson, Nick;Cui, Haiyan;Gimbel, Mark I;Wilson, Melissa A;Buetow, Kenneth H;Roe, Denise J;DiCaudo, David J;Homsi, Jade;Hastings, Karen Taraszka
通讯作者：
Hastings, Karen Taraszka

Shared Gene Expression and Immune Pathway Changes Associated with Progression from Nevi to Melanoma.

与从痣到黑色素瘤进展相关的共同基因表达和免疫途径变化。

DOI：
发表时间：
2021-12-21
期刊：
影响因子：
5.2
作者：
Borden, Elizabeth S;Adams, Anngela C;Buetow, Kenneth H;Wilson, Melissa A;Bauman, Julie E;Curiel;Chow, H;LaFleur, Bonnie J;Hastings, Karen Taraszka
通讯作者：
Hastings, Karen Taraszka

Cancer Neoantigens: Challenges and Future Directions for Prediction, Prioritization, and Validation.

癌症新抗原：预测、优先排序和验证的挑战和未来方向。