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细胞反应的调节对改善癌症免疫疗法有很大的希望具有免疫检查点抑制，癌症疫苗和过继的T细胞疗法。对免疫疗法需要T细胞识别来自癌细胞的突变肽表位，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细胞识别由MHC II类提出的新抗原。但是，实验或用于鉴定免疫原性的MHC II类新抗原的计算方法（引起T细胞响应）尚未建立完善。而肿瘤特异性的CD4 T细胞表位对于产生有效的抗肿瘤T细胞对免疫疗法的反应，CD4调节t（Treg）细胞在内部发展肿瘤抑制其他T细胞的增殖和功能。破坏CD4 Treg细胞是一个有前途的免疫治疗方法。但是，缺乏专门针对和破坏肿瘤特异性的方法 CD4 Treg细胞可防止Treg细胞的耗竭在癌症的临床试验中进一步前进免疫疗法。肽-MHC四聚体可用于鉴定肿瘤特异性T细胞。但是，肽-MHC 对于许多已知引起T细胞反应的肽抗原，无法生成II类四聚体肽与MHC II类相互作用的低亲和力或稳定性。该提议将推动通过解决知识的三个差距：1）无法使用四聚体鉴定大多数肿瘤 - 特定的CD4 T细胞，2）无法靶向肿瘤特异性Treg细胞破坏，3）缺乏实验性和计算工具，以优先考虑免疫原性的MHC II类新抗原。该建议将利用一个新的仿生5模块嵌合抗原受体（5MCAR）的专利技术。 5MCAR由肽MHC II类的外生域与T细胞的跨膜和细胞质结构域融合受体，促进与CD3信号复合复合物和替代共核能组成的受体 CD80融合到SRC激酶LCK。 5MCAR在细胞毒性T细胞上表达。通过5MCAR发出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的II类。中心假设是5MCAR将有助于确定免疫原性MHC II类黑色素瘤新抗原并通过破坏肿瘤特异性CD4有效治疗黑色素瘤肿瘤 Treg细胞。该建议的目的是鉴定免疫原性MHC II类新抗原并测试功效使用临床相关的免疫原性来治疗黑色素瘤中耗尽新抗原特异性CD4细胞小鼠黑色素瘤模型。具有5MCAR的基于细胞的测定将用于高吞吐量筛选肽文库以识别MHC II类新抗原，从而引起CD4常规T细胞和调节t 黑色素瘤肿瘤中的细胞反应。肿瘤特异性5MCAR T细胞在治疗已建立的疗效黑色素瘤肿瘤单独通过新抗原特异性Treg细胞耗尽并与免疫结合将评估使用抗PD-1的检查点抑制。使用生成的综合，公正的数据集通过测试所有错义突变的免疫原性，这是一种预测免疫原性的计算模型将创建和验证MHC II类新抗原。该提议的影响是1）建立一个西班牙裔服务机构的亚利桑那大学与库恩斯博士合作，2）技术创新以允许高吞吐量筛选以鉴定免疫原性MHC II类新抗原，有针对性破坏肿瘤特异性CD4 Treg细胞，并改善了用于的计算方法免疫原性MHC II类新抗原的优先次序，3）增加优异奖的影响解决当前知识中的差距，以防止癌症免疫疗法的进步，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从事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）

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

DOI：
10.3390/cancers14092200
发表时间：
2022-04-28
期刊：
CANCERS
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.

DOI：
10.3390/cancers14010003
发表时间：
2021-12-21
期刊：
Cancers
影响因子：
5.2
作者：
Borden ES;Adams AC;Buetow KH;Wilson MA;Bauman JE;Curiel-Lewandrowski C;Chow HS;LaFleur BJ;Hastings KT
通讯作者：
Hastings KT

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