MHC class II antigen presentation in melanoma: impact on immune recognition

黑色素瘤中 MHC II 类抗原呈递：对免疫识别的影响

• 批准号: 10618790
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618790
• 关键词: Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Area; Biological; CD8-Positive T-Lymphocytes; Cancer Patient; Combined Modality Therapy; Data; Development; Enzymes; Exhibits; Exposure to; Genomics; Goals; Health; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Immune; Immune mediated destruction; Immune system; Immunologics; Immunotherapy; Incidence; Knowledge; Laboratories; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Melanoma Cell; Military Personnel; Mutation; Neoplasm Metastasis; Occupational Exposure; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Research; Research Priority; Resistance; Risk Factors; Role; Specimen; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Training; Treatment Efficacy; Tumor Antigens; UV Radiation Exposure; Ultraviolet Rays; Veterans; active duty; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; antigen processing; cancer infiltrating T cells; cancer therapy; cancer type; cell type; clinically relevant; immune checkpoint blockade; immunogenic; immunoregulation; improved; in vivo; interest; melanoma; member; military service; military veteran; mouse model; neoplastic cell; novel; novel strategies; personalized medicine; precision medicine; protein complex; response; service member; side effect; therapy resistant; treatment response; tumor; tumor growth

Anti-tumor immune responses depend on T cell recognition of tumor antigens in the context of major histocompatibility complex (MHC) proteins to destroy tumors. While the MHC class I antigen presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors, the function of the MHC class II antigen presentation pathway in melanoma cells is not well understood. The goal of this proposal is to determine the function of MHC class II and the MHC class II antigen processing enzyme, GILT, in melanoma cells in regulating the anti-tumor immune response and response to immunotherapy. Preliminary results from the laboratory of the PI revealed that the MHC class II antigen presentation pathway and GILT, an enzyme involved in MHC class II antigen processing, are associated with improved survival in melanoma. Recent data from other groups show that induction of MHC class II expression on melanoma cells is associated with improved response to immune checkpoint blockade with anti-PD-1 in retrospective analyses. Immune checkpoint blockade with anti-PD-1 is being used to treat a rapidly growing number of cancer types and patients. Yet, the challenge remains that at least 60% and 25% of melanoma patients exhibit primary and acquired resistance to this therapy, respectively. The central hypothesis of this proposal is that the MHC class II antigen presentation pathway in melanoma cells enhances T cell-mediated destruction of tumors and improves the response to immune checkpoint blockade. To test this hypothesis clinically-relevant, immunogenic mouse models of melanoma will be employed to determine the role of GILT and MHC class II in melanoma cells on regulating the anti-tumor immune response and response to immunotherapy. This research team will determine the immunomodulatory effects of GILT and MHC class II expression in melanoma cells and identify immune cell types required for the modulation of tumor growth. Impact: New knowledge gained from the completion of these studies is anticipated to lead to improved patient outcomes. Determining the biological basis for MHC class II pathway members in the anti-tumor immune response and response to immunotherapy is expected to 1) identify novel causal determinants of immunologically hot vs. cold tumors, 2) provide support for a personalized medicine approach to optimize immunotherapy efficacy and limit side effects, and 3) define a novel pathway controlling anti-tumor immune responses that can be manipulated to augment treatment efficacy. The results of these studies are anticipated to be broadly applicable, as many cancers express MHC class II and all cancer types share the challenge of resistance to immunotherapy.

抗肿瘤免疫应答依赖于T细胞在主要肿瘤免疫应答的背景下对肿瘤抗原的识别。 组织相容性复合体（MHC）蛋白破坏肿瘤。虽然MHC I类抗原呈递 在黑色素瘤细胞中的免疫途径在免疫介导的肿瘤破坏中具有公认的作用， 在黑色素瘤细胞中的MHC II类抗原呈递途径还没有很好的理解。这个目标 建议是确定MHC II类和MHC II类抗原加工酶，GILT， 在黑色素瘤细胞中调节抗肿瘤免疫应答和对免疫疗法的应答。初步 PI实验室的结果显示，MHC II类抗原呈递途径和GILT， 参与MHC II类抗原加工的酶与改善黑素瘤的存活率相关。 来自其他研究组的最新数据表明，诱导黑色素瘤细胞上的MHC II类表达是一个非常重要的因素。 与在回顾性分析中对抗PD-1的免疫检查点阻断的应答改善相关。 使用抗PD-1的免疫检查点阻断正在用于治疗快速增长的癌症类型 和病人。然而，挑战仍然存在，至少60%和25%的黑色素瘤患者表现出原发性和非原发性黑色素瘤。 获得性耐药。该提议的核心假设是， 黑素瘤细胞中的II类抗原呈递途径增强T细胞介导的肿瘤破坏， 改善对免疫检查点阻断的反应。为了检验这一假设的临床相关性， 将使用黑色素瘤的免疫原性小鼠模型来确定GILT和MHC II类在 黑色素瘤细胞调节抗肿瘤免疫应答和对免疫疗法的应答。本研究 研究小组将确定GILT和MHCII类表达在黑色素瘤细胞中的免疫调节作用 并鉴定调节肿瘤生长所需的免疫细胞类型。影响：获得的新知识 这些研究的完成预计将改善患者的预后。确定 MHC II类分子通路成员在抗肿瘤免疫应答和抗肿瘤免疫应答中的生物学基础 免疫疗法有望1）鉴定免疫学上热肿瘤与冷肿瘤的新的因果决定因素，2） 为个性化医疗方法提供支持，以优化免疫治疗疗效并限制副作用 作用，和3）定义了一种控制抗肿瘤免疫应答的新途径， 提高治疗效果。这些研究的结果预计将广泛适用，因为许多 癌症表达MHCII类，并且所有癌症类型都面临免疫疗法抗性的挑战。