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

抗肿瘤免疫反应依赖于T细胞对肿瘤抗原的识别 组织相容性复合体(MHC)蛋白可破坏肿瘤。而MHC-I类抗原呈递 黑色素瘤细胞中的通路在免疫介导的肿瘤破坏中具有公认的作用，其功能 黑色素瘤细胞中MHC-II类抗原提呈途径的研究还不是很清楚。这样做的目的是 建议确定MHC II类和MHC II类抗原处理酶、GILT、 在黑色素瘤细胞中调节抗肿瘤免疫反应和免疫治疗反应。初步 PI实验室的结果显示，MHC-II类抗原提呈途径和GILT，以及 参与MHC-II类抗原处理的酶与提高黑色素瘤的存活率有关。 来自其他研究小组的最新数据显示，诱导黑色素瘤细胞表达MHC-II是 在回顾性分析中，与抗PD-1抗体阻断免疫检查点的反应改善有关。 带有抗PD-1抗体的免疫检查点阻断正被用于治疗数量迅速增加的癌症类型 和病人。然而，挑战仍然是，至少60%和25%的黑色素瘤患者表现出原发和 分别对该疗法产生获得性耐药。这一提议的中心假设是，MHC 黑色素瘤细胞中II类抗原提呈通路增强T细胞介导的肿瘤杀伤作用 提高对免疫检查点封锁的响应。为了验证这一假设在临床上的相关性， 免疫原性小鼠黑色素瘤模型将被用来确定GILT和MHC II类分子在 黑色素瘤细胞对调节抗肿瘤免疫反应和免疫治疗的反应。这项研究 研究小组将确定GILT和黑色素瘤细胞MHC-II类表达的免疫调节作用 并确定调节肿瘤生长所需的免疫细胞类型。影响：获得新知识 这些研究的完成预计将导致患者预后的改善。确定 MHC-II类通路成员在抗肿瘤免疫应答中的生物学基础 免疫治疗有望1)识别免疫热性肿瘤与冷热性肿瘤的新的致病决定因素，2) 为个性化医学方法提供支持，以优化免疫治疗效果和限制副作用 效应，以及3)定义了一种新的控制抗肿瘤免疫反应的途径，可以被操纵 增强治疗效果。这些研究的结果预计将广泛适用，因为许多 癌症表达第二类MHC，所有类型的癌症都面临着免疫治疗耐药的挑战。

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.