Neoantigen-specific T cells in a novel cutaneous squamous cell carcinoma model

新型皮肤鳞状细胞癌模型中的新抗原特异性 T 细胞

• 批准号: 10602966
• 负责人: Anngela Christina Adams
• 金额: $ 5.27万
• 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: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602966
• 关键词: Address; Adoptive Transfer; Affinity; Antibodies; Binding; Bioinformatics; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Characteristics; Complex; Data; Dendritic Cells; Dermatologist; Development; Diagnosis; Flow Cytometry; Foundations; Generations; Goals; Growth; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunologics; Immunotherapeutic agent; Inbred BALB C Mice; Injections; Irradiated tumor; Laboratories; Light; MHC Class I Genes; MHC Class II Genes; MHC antigen; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Modeling; Mus; Mutation; Neoplasm Metastasis; Nude Mice; Outcome; Pathway interactions; Patients; Persons; Physiological; Research; Role; Skin Cancer; Skin Carcinoma; Stains; T cell response; T-Lymphocyte; Techniques; Transplantation; Vaccinated; Vaccination; Wild Type Mouse; anti-PD-1; anti-PD1 therapy; antigen-specific T cells; cancer type; cancer vaccination; comparative efficacy; cytotoxic CD8 T cells; exome sequencing; immunogenic; immunogenicity; improved; improved outcome; in vitro testing; in vivo; innovation; melanoma; mouse model; neoantigen vaccine; neoantigens; neoplastic cell; novel; novel drug class; prevent; programmed cell death protein 1; receptor; response; skin squamous cell carcinoma; success; transcriptome sequencing; transplant model; treatment response; tumor; tumor growth; vaccination strategy; vaccine strategy

Abstract: More than one million cases of cutaneous squamous cell carcinoma (cSCC) are diagnosed annually in the US and approximately 4% of patients develop metastases and 2% die of cSCC; thus, a similar number of people die each year from cSCC as melanoma. Immune checkpoint inhibitors (ICI) are a new class of drugs that have transformed the therapy of multiple cancer types, but only half of cSCC patients respond to ICI treatment. ICI target receptors on T cells, such as PD-1, that are expressed after activation and function to turn off T cell responses. The response of cSCC patients to ICI demonstrates the ability of T cells to constrain cSCC growth. However, it remains unclear the extent to which CD8 and, in particular, CD4 T cells contribute to immune-mediated control of cSCC. While the focus of anti-tumor T cell responses has been on MHC class I neoantigens that elicit cytotoxic CD8 T cell responses, there is growing evidence that MHC class II neoantigens eliciting CD4 T cell responses are critical in constraining tumor growth and enhancing response to ICI. Thus, there is a critical need to understand the role of CD8 and CD4 T cells, especially the role of neoantigen-specific T cells, in controlling cSCC growth. We generated a novel physiologic cSCC transplantable model on the BALB/c background from a solar simulated light-induced invasive cSCC tumor. Preliminary data supports that T cells constrain the in vivo tumor growth in the cSCC model and that this model is sensitive to anti-PD-1 treatment. Using bioinformatic approaches with whole exome and RNA sequencing data, we have identified immunogenic MHC class I and II neoantigens predicted to elicit a T cell response based on the binding affinity and presentation of the neoantigen:MHC complex and neoantigen expression. Using melanoma patient data, our lab has previously demonstrated that these characteristics accurately predict the ability of a neoantigen to elicit a T cell response. The central hypothesis is that both neoantigen- specific CD8 and CD4 T cells contribute to immune-mediated control of cSCC growth and response to treatment with vaccination with immunogenic neoantigens alone or in combination with anti-PD-1. To address this hypothesis, we will determine the role of CD8 and CD4 T cells in controlling tumor growth, identify MHC class I and II neoantigens that elicit in vivo T cell responses, and evaluate the expression of functional and inhibitory neoantigen-specific CD8 and CD4 T cells throughout cSCC tumor growth. Then, we will vaccinate mice with dendritic cells loaded with irradiated tumor cells or immunogenic MHC class I and/or II neoantigens and compare the efficacy of these vaccination strategies in inducing CD8 and/or CD4 T cells to prevent cSCC growth and treat cSCC alone or in combination with anti-PD-1. We will demonstrate the requirement for CD8 and/or CD4 T cells through antibody depletion and adoptive transfer. The impact of this project is to 1) identify the contributions of neoantigen-specific CD8 and CD4 T cells in control of cSCC growth and 2) advance the application of personalized neoantigen vaccines to treat cSCC alone or in combination with anti-PD-1.

摘要：每年被诊断出超过一百万个皮肤鳞状细胞癌（CSCC） 在美国和大约4％的患者发生转移和2％的CSCC死亡；因此，一个类似的数字 人们每年都死于CSCC作为黑色素瘤。免疫检查点抑制剂（ICI）是一类新的药物 改变了多种癌症类型的治疗，但只有一半的CSCC患者对ICI有反应 治疗。 T细胞上的ICI靶向受体，例如PD-1，在激活和功能转动后表达 关闭T细胞反应。 CSCC患者对ICI的反应证明了T细胞约束的能力 CSCC增长。但是，尚不清楚CD8及其CD4 T细胞在多大程度上有助于 免疫介导的CSCC控制。抗肿瘤T细胞反应的重点已成为MHC I类 引起细胞毒性CD8 T细胞反应的新抗原，越来越多的证据表明MHC II类 引起CD4 T细胞反应的新抗原对于约束肿瘤生长和增强对的反应至关重要 ICI。因此，迫切需要了解CD8和CD4 T细胞的作用，尤其是 新抗原特异性T细胞，控制CSCC生长。我们生成了一种新颖的生理CSCC 来自太阳能模拟光诱导的侵入性CSCC肿瘤的BALB/C背景上的可移植模型。 初步数据支持T细胞限制CSCC模型中体内肿瘤的生长，并且该模型 对抗PD-1治疗敏感。使用整个外显子组和RNA测序的生物信息学方法 数据，我们已经确定了免疫原性的I类和II类新抗原，预测会引起T细胞反应 基于新抗原的结合亲和力和呈现：MHC复合物和新抗原表达。 使用黑色素瘤患者数据，我们的实验室先前已经证明了这些特征准确 预测新抗原引起T细胞反应的能力。中心假设是两个新抗原 特定的CD8和CD4 T细胞有助于免疫介导的CSCC生长的控制和对 单独使用免疫原性新抗原或与抗PD-1结合进行疫苗接种治疗。解决 这个假设，我们将确定CD8和CD4 T细胞在控制肿瘤生长中的作用，鉴定MHC I级和II级新抗原，引起体内T细胞反应，并评估功能和功能的表达 在CSCC肿瘤生长中，抑制性新抗原特异性CD8和CD4 T细胞。然后，我们将接种疫苗 带有辐照的肿瘤细胞或免疫原性的MHC I和/或II新抗原的小鼠的小鼠 并比较这些疫苗接种策略在诱导CD8和/或CD4 T细胞中的功效 单独或与抗PD-1结合生长和治疗CSCC。我们将证明CD8的要求 和/或CD4 T细胞通过抗体耗竭和过继转移。该项目的影响是1）确定 新抗原特异性CD8和CD4 T细胞在控制CSCC生长方面的贡献，2） 个性化新抗原疫苗的应用单独或与抗PD-1结合治疗CSCC。