T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

摘要 这一紧急补充资料正在解决癌症治疗和PD-1阻断在 特别是对新冠肺炎感染和疫苗接种的免疫反应。母公司的主要目标 题为“T细胞抵抗PD-1检查点封锁的内在机制”的提案是 T细胞受体在PD-1检查点抗性分子机制中的作用 封锁。 新冠肺炎大流行突显了对有效疫苗和治疗的迫切需要，特别是在 免疫功能受损的个人，包括大多数癌症患者。之前报道的动物数据 对冠状病毒(CoV)的疫苗接种，包括SARS-CoV，表明肠外或肌肉内注射 主要激活系统免疫的免疫接种可能不足以预防这些疾病和 其他呼吸道感染。由于呼吸道粘膜是冠状病毒的主要目标，它一直是 证明了有针对性的粘膜免疫可能是一种更有效的策略，因为它涉及到 激活所有类型的适应性免疫：系统、粘膜和细胞免疫。已经证明，抗药性 小鼠抗SARS冠状病毒感染主要由以常驻记忆T细胞为代表的细胞免疫所驱动 细胞。在人类中，在SARS的外周血液中检测到了SARS-CoV特异性的记忆T细胞 患者感染后六年或更长时间，尽管缺乏病毒特异性记忆B细胞。我们假设 (1)对包括SARS-CoV2在内的冠状病毒的长期保护可以通过一种粘膜疫苗来实现 持久的细胞免疫和(2)检查站封锁可以提高新冠肺炎期间的T细胞应答 接种疫苗。在这项对父母拨款的补充中，我们建议确定SARS-CoV2特异性T细胞表位 在癌症患者和健康人中(目标1)，并在工程中利用最具免疫原性的表位 重组疫苗文库(目标2)。由于短肽表位是很差的免疫原，我们将利用一个 无毒的霍乱毒素B(CTB)蛋白作为粘膜佐剂和靶向递送的载体 免疫原至肺树突状细胞(目标2)。接下来，将对疫苗文库进行免疫原性测试 用有无PD-1阻断的小鼠模型评价检查点阻断对T细胞的影响 在接种疫苗期间激活。最有效的疫苗原型将使用SARS-CoV2进一步验证 小鼠模型(目的3)。该项目将有助于评估T细胞在新冠肺炎免疫中的作用 个体和癌症患者，测试一种新型疫苗的有效性，在体内小鼠模型和 确定PD-1阻断在T细胞免疫应答中的作用。

Abstract This Urgent Supplement is addressing the possible effects of cancer therapies, and PD-1 blockade in particular, on immune responses to COVID-19 infection and vaccination. The primary objective of the parent proposal CA243486 entitled “T cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade” is to determine the function of T cell receptors in the molecular mechanism of resistance to PD-1 checkpoint blockade. The COVID-19 pandemic underscores the urgent need for effective vaccines and treatments, especially in immunocompromised individuals including majority of cancer patients. Previously reported data on animal vaccination against coronaviruses (CoV), including SARS-CoV, demonstrated that parenteral or intramuscular immunization, which predominantly activates systemic immunity, may be inadequate in prevention of these and other respiratory tract infections. Since respiratory mucosa is a primary target for CoV, it has been demonstrated that targeted mucosal immunization could be a much more effective strategy as it involves activation of all types of adaptive immunity: systemic, mucosal and cellular. It has been shown that resistance to SARS-CoV infection in mice is primarily driven by cellular immunity represented by the resident memory T cells. In humans, SARS-CoV-specific memory T cells have been detected in the peripheral blood of SARS patients six or more years post-infection despite the lack of virus-specific memory B cells. We hypothesize that (1) the long-term protection against CoV including SARS-CoV2 can be achieved by a mucosal vaccine eliciting long-lasting cellular immunity and (2) checkpoint blockade can elevate the T cell response during COVID-19 vaccination. In this supplement to our parent grant we propose to identify SARS-CoV2 specific T cell epitopes in cancer patients and healthy individuals (Aim 1) and utilize the most immunogenic epitopes in engineering of a recombinant vaccine library (Aim 2). Since short peptide epitopes are poor immunogens, we will utilize a non-toxic cholera toxin B (CTB) protein as a mucosal adjuvant and as a carrier for targeted delivery of immunogens to the lung dendritic cells (Aim 2). Next, the vaccine library will be tested for immunogenicity using mouse models with and without PD-1 blockade to evaluate the effect of checkpoint blockade on T cell activation during vaccination. The most efficient vaccine prototype will be further validated using a SARS-CoV2 mouse model (Aim 3). This project will help to evaluate the role of T cells in immunity to COVID-19 in healthy individuals and cancer patients, test the efficacy of a novel vaccine using in in vivo mouse model and determine the role of PD-1 blockade in T cell response to immunization.