Immunoediting in Cutaneous Squamous Cell Carcinoma

皮肤鳞状细胞癌的免疫编辑

• 批准号: 10676479
• 负责人: Elizabeth Borden
• 金额: $ 4.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676479
• 关键词: Actinic keratosis; Antigen Presentation; Antigen Presentation Pathway; Area; Binding Proteins; Cancer Model; Cancer Vaccines; Carcinogen exposure; Cell Fraction; Cell physiology; Clinical; Cytoprotection; Data; Development; Genetic; Human; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunocompromised Host; Immunologist; Immunotherapy; Incidence; Individual; Irradiated tumor; Laboratories; Lesion; Light; MHC Class I Genes; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mentorship; Missense Mutation; Modeling; Mus; Mutate; Nude Mice; Pathway interactions; Patients; Peptides; Process; Recurrence; Research; Resistance; Role; Shapes; Skin; Skin Cancer; Solid; Systemic Therapy; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Tacrolimus; Testing; Tissues; Transplant Recipients; Transplantation; Vaccination; Vaccines; Work; cancer cell; cancer immunotherapy; checkpoint inhibition; efficacy testing; high risk; immune cell infiltrate; immunogenic; immunogenicity; immunosuppressed; innovation; neoantigen vaccine; neoantigens; neoplastic cell; novel strategies; organ transplant recipient; preservation; response; skin squamous cell carcinoma; targeted treatment; transplant model; tumor; vaccine efficacy; vaccine evaluation

PROJECT SUMMARY: Immunosuppressed transplant recipients have a 65-253 fold higher risk of developing cutaneous squamous cell carcinoma (cSCC) and are contraindicated for treatment with immune checkpoint inhibitors, presenting an important unmet clinical need. The ability of T cells to constrain cSCC is demonstrated by the response of 32- 46% of immunocompetent patients to immune checkpoint inhibitors. However, cSCC has the potential to evade an active T cell response as demonstrated by the formation of cSCC in immunocompetent patients and resistance to immune checkpoint inhibition in some patients. Prior work suggests that evasion of an active T cell response occurs through the process of immunoediting, in which T cells destroy tumors that present mutated tumor proteins that bind the T cell receptor (neoantigens), and thus select for less immunogenic tumors. This proposal will compare the neoantigen profile and immune escape mechanisms in tumors and tumor-adjacent skin from immunosuppressed and immunocompetent individuals as a novel approach to evaluate the role of T cells in immunoediting. Evaluating the neoantigen profile in carcinogen-exposed tumor- adjacent skin will additionally provide evidence for immunoediting before the formation of a clinically apparent lesion. Furthermore, since cSCC in immunosuppressed patients develops in the context of diminished T cell function, this proposal tests the innovative concept that these patients will have a neoantigen profile that is more amenable to treatment with a personalized neoantigen vaccine. The Hastings laboratory has created an MHC class I neoantigen prioritization model with high accuracy in predicting neoantigens that elicit a T cell response, which will be applied to evaluate the neoantigen profiles of cSCC from immunosuppressed and immunocompetent individuals. The Hastings laboratory has also generated and characterized a solar- simulated light induced, transplantable cSCC tumor that will be used to test vaccine efficacy in the proposed studies. Preliminary data demonstrate that the cSCC transplantable model is constrained by T cells and vaccination with irradiated tumor cells protects from tumor challenge. This proposal will test the central hypothesis that cSCC and carcinogen-exposed, tumor-adjacent skin from immunosuppressed individuals will have a more immunogenic neoantigen profile and less frequent immune escape mechanisms compared to cSCC from immunocompetent individuals. Aim 1 of this proposal will compare the neoantigen profile and immune escape mechanisms between immunosuppressed and immunocompetent patients. Aim 2 will compare the neoantigen profile and immune escape mechanisms of cSCC from mice with and without a functional T cell repertoire and demonstrate the efficacy of cancer vaccines in immunosuppressed mice. The impact of the project is to provide evidence for neoantigen vaccines as an important treatment option for immunosuppressed patients and systematically characterize the immune escape mechanisms in cSCC to determine additional targets of therapy for cSCC in immunocompetent patients.

项目概要： 免疫抑制移植受者发生皮肤鳞状细胞癌的风险高65-253倍。 细胞癌（cSCC），禁忌使用免疫检查点抑制剂治疗， 重要的未满足的临床需求。T细胞抑制cSCC的能力通过32-HT 3的应答来证明。 46%的免疫功能正常的患者使用免疫检查点抑制剂。然而，cSCC有可能规避 免疫活性患者中cSCC的形成证明了活跃的T细胞应答， 免疫检查点抑制在某些患者中的抵抗。先前的研究表明，逃避一个活跃的T 细胞反应通过免疫编辑过程发生，在该过程中T细胞破坏存在的肿瘤。 突变的肿瘤蛋白结合T细胞受体（新抗原），从而选择免疫原性较低的 肿瘤的该提案将比较肿瘤中的新抗原谱和免疫逃逸机制， 作为一种新的方法， 评估T细胞在免疫编辑中的作用。评价致癌物暴露肿瘤中的新抗原谱- 邻近皮肤将另外提供在形成临床上明显的免疫编辑之前进行免疫编辑的证据。 损伤。此外，由于免疫抑制患者的cSCC是在T细胞减少的背景下发展的， 功能，该提案测试了这些患者将具有新抗原谱的创新概念， 更适合用个性化的新抗原疫苗治疗。黑斯廷斯实验室创造了一种 MHC I类新抗原优先化模型在预测引发T细胞免疫应答的新抗原中具有高准确性 反应，这将被应用于评估cSCC的免疫抑制和 免疫活性个体。黑斯廷斯实验室还生成并表征了太阳能- 模拟光诱导的可移植cSCC肿瘤，将用于测试疫苗的有效性， 问题研究初步数据表明，cSCC可移植模型受到T细胞的限制， 用经照射的肿瘤细胞进行疫苗接种保护免受肿瘤攻击。这一提议将考验中央 假设免疫抑制个体的cSCC和致癌物暴露的肿瘤相邻皮肤将 具有更高的免疫原性新抗原谱和更少的免疫逃逸机制， 来自免疫活性个体的cSCC。本提案的目的1将比较新抗原谱和 免疫抑制和免疫功能正常患者之间的免疫逃逸机制。目标2将 比较了有和没有免疫抑制剂的小鼠cSCC的新抗原谱和免疫逃逸机制， 功能性T细胞库，并证明癌症疫苗在免疫抑制小鼠中的功效。的 该项目的影响是为新抗原疫苗作为一种重要的治疗选择提供证据， 免疫抑制患者，并系统地描述cSCC中的免疫逃逸机制， 确定免疫功能正常患者cSCC治疗的其他靶点。