Innate Antiviral Signals for Cancer Immunotherapy

WHO IV级恶性胶质瘤是大多数癌症的标志，在那里免疫的疗效 检查点封锁受到低突变负担和臭名昭著的免疫抑制的阻碍 不参与的肿瘤微环境。要克服这些障碍并实现成功的免疫治疗 恶性胶质瘤(或其他非免疫原性癌症)，新的治疗方法必须能够在免疫学上 利用肿瘤微环境(TME)激发新的抗肿瘤免疫系统。我们的项目是 专注于脊髓灰质炎：鼻病毒嵌合体PVSRIPO，以及它在 我也是。PVSRIPO在单次对流增强肿瘤内注射后产生有希望的反应 有复发的WHO IV级恶性胶质瘤。它以肿瘤细胞为靶标，通过感染和破坏 其受体CD155肿瘤抗原在这些细胞上的异位表达。然而，我们假设， PVSRIPO免疫治疗潜力的关键是脊髓灰质炎病毒对抗原提呈细胞的固有趋向性 (APC)，例如肿瘤相关巨噬细胞，以及对天然抗病毒干扰素(干扰素)的特殊抵抗力 回应。PVSRIPO感染APC引起亚致死性病毒繁殖，引发深刻、持续的 I型干扰素反应并刺激T细胞共刺激功能。人们普遍认为， APC对先天抗病毒反应的无与伦比的刺激是产生肿瘤抗原特异性的关键 抗肿瘤免疫。与APC在自然脊髓灰质炎病毒感染中的作用一样，PVSRIPO的性质和范围 体内肿瘤中与髓系宿主细胞的相互作用尚不清楚。例如，允许 APC细胞毒性减弱的慢性PVSRIPO复制--其干扰素占优势的必要前奏 激活--保持模糊状态。这一项目中提出的研究对临床非常重要。 PVSRIPO免疫治疗在恶性胶质瘤及其他肿瘤中的研究进展。因此，我们正在追求 以下具体目标：1)确定PVSRIPO翻译能力、细胞毒性和 巨噬细胞/髓系细胞诱生I型干扰素。我们将在人类髓系细胞中进行研究 巨噬细胞机械破译PVSRIPO与APC的独特关系；2)解开 PVSRIPO对脑胶质瘤TME内巨噬细胞/髓系细胞重新编程的潜能 巨噬细胞在PVSRIPO免疫治疗中的作用我们将使用可移植的化学诱导-和 基因工程免疫活性小鼠脑胶质瘤模型研究肿瘤间质在肿瘤中的作用 PVSRIPO诱导的抗肿瘤免疫；3)阐明PVSRIPO靶向巨噬细胞/髓系细胞 原代人胶质母细胞瘤外植体，并在体外检测促炎重编程。我们会破译 新鲜、未分离的胶质瘤患者原代组织块对PVSRIPO感染的TME反应 并测量其在克服T细胞抑制方面的潜力。

WHO grade IV malignant glioma is emblematic for a majority of cancers, where the efficacy of immune checkpoint blockade is impeded by a low mutational burden and notorious immunosuppression incited by a non-engaged tumor microenvironment. To overcome these hurdles and achieve successful immunotherapy of malignant glioma (or other `non-immunogenic' cancers), novel approaches must be capable of immunologically engaging the tumor microenvironment (TME) to instigate new antitumor immune repertoire. Our project is focused on the polio:rhinovirus chimera PVSRIPO, and its capacity to elicit inflammatory responses in the TME. PVSRIPO yields promising responses after single, convection-enhanced intratumoral infusion in patients with recurrent WHO grade IV malignant glioma. It targets neoplastic cells for infection and destruction by virtue of ectopic expression of its receptor, the CD155 tumor antigen, on such cells. We hypothesize, however, that the key to PVSRIPO's immunotherapy potential is poliovirus' inherent tropism for antigen presenting cells (APCs), e.g. tumor-associated macrophages, and a peculiar resistance to the innate antiviral interferon (IFN) response. PVSRIPO infection of APCs elicits sublethal viral propagation that provokes profound, sustained type I IFN responses and stimulates T cell co-stimulating functions. There is broad agreement that the unparalleled stimulus of the innate antiviral response in APCs is pivotal for generating tumor antigen-specific antitumor immunity. As with the role of APCs in natural poliovirus infection, the nature and extent of PVSRIPO interactions with myeloid host cells in tumors in vivo are unknown. For example, the mechanisms permitting chronic PVSRIPO replication with subdued cytotoxicity in APCs -necessary preludes to their IFN-dominant activation- remain obscure. The investigations proposed in this project are of utmost importance for the clinical development of PVSRIPO immunotherapy in malignant gliomas and beyond. Therefore, we are pursuing the following Specific Aims: 1) Define the molecular basis for PVSRIPO translation competency, cytotoxicity and type I IFN induction in macrophages/myeloid cells. We will perform studies in human myeloid-derived macrophages to mechanistically decipher the unique relationship of PVSRIPO with APCs; 2) Unravel PVSRIPO's potential for reprogramming macrophages/myeloid cells in the glioma TME in vivo and determine the role of macrophages in PVSRIPO immunotherapy. We will use transplantable chemically-induced- and genetically-engineered immunocompetent mouse glioma models to investigate the role of tumor stroma in PVSRIPO-instigated antitumor immunity; 3) Elucidate PVSRIPO targeting of macrophages/myeloid cells in primary human glioblastoma explants and examine proinflammatory reprogramming in vitro. We will decipher the TME response to PVSRIPO infection in fresh, non-dissociated primary tissue explants from glioma patients and measure its potential in overcoming T cell suppression.