Reviving cancer immune surveillance with CD4 T cell help

摘要 免疫系统能够消除晚期恶性肿瘤，但癌症免疫治疗取得成功。 仅限于癌症类型的一部分。传统的CD4，或‘辅助’，T细胞发挥着不可或缺的作用 协调免疫反应，并可增强抗肿瘤免疫功能：通过激活和 抗原提呈细胞功能和抗肿瘤CD8 T细胞的增强。我的博士后工作证明了 在瘤内注射Recall抗原(例如脊髓灰质炎)后，重新激活儿童疫苗特异性的CD4T细胞 衣壳或破伤风类毒素)，介导抗肿瘤效果，并在体内引起先天和获得性炎症 肿瘤。肿瘤内回忆反应的抗肿瘤效果部分依赖于CD8T细胞，并且 与表型不同于肿瘤相关的活化粒细胞巨噬细胞的浸润相吻合 Poly IC直接天然刺激后的巨噬细胞。因此，诱导CD4T细胞召回代表了一种新的 治疗机会，具有独特的发炎和抗肿瘤潜力。我们假设 肿瘤内儿童疫苗特异性的CD4T细胞召回反应激发明显和持久的炎症 重新编程髓系细胞以增强抗肿瘤CD8 T细胞功能并介导抗肿瘤效果。至 检验这一假说，我们将定义在触发瘤内回忆反应后先天免疫的重新编程 并确定其在介导抗肿瘤疗效(目标1)中的作用，并测试脊髓灰质炎疫苗特异性CD4T细胞是否召回 应答‘帮助’抗肿瘤CD8 T细胞(目标2)。这些分析将为临床上可操作的路线开发提供信息 回想一下在肿瘤内获得CD4T细胞帮助的基于抗原的疗法(独立的R00阶段的目标)。 这些发现的临床翻译将通过确定治疗策略来获得信息，例如联合 先天模式识别受体激动剂治疗，可与召回抗原协同介导系统性 抗肿瘤疗效；以及确定更有针对性的分子途径来概括CD4T细胞在肿瘤中的帮助 治疗(目标3)。这项工作的K99阶段将由几位著名的肿瘤专家指导 免疫生物学和癌症免疫治疗：包括Darell Bigner博士(癌症免疫治疗的主要导师 脑肿瘤)、西蒙·格雷戈里(计算专家)、齐静丽(使用转录组分析的T细胞生物学家 以评估T细胞功能)，艾米·海姆伯格(肿瘤相关髓系细胞专家，之前曾应用 转录组分析以确定肿瘤相关髓系细胞的激活/抑制特征)，以及James Herndon II(生物统计学支持)。这项提议将使召回抗原在临床上转化为癌症。 并将启动一项利用CD4T细胞强大的免疫刺激作用的研究计划 帮助开发新的癌症疗法。

Abstract The immune system is capable of eliminating advanced malignant tumors, yet cancer immunotherapy success has been limited to a subset of cancer types. Conventional CD4, or `helper', T cells play an integral role in orchestrating immune responses, and can potentiate the function of antitumor immunity: both via activation and potentiation of antigen presenting cell function and antitumor CD8 T cells. My postdoctoral work demonstrated that reactivating childhood vaccine-specific CD4 T cells after intratumor injection of recall antigen (e.g. polio capsid or tetanus toxoid), mediates antitumor efficacy and causes both innate and adaptive inflammation within tumors. The antitumor efficacy of intratumor recall responses were partially dependent upon CD8 T cells, and coincided with infiltration of activated granulocytic macrophages with phenotypes distinct from tumor associated macrophages after direct innate stimulation with Poly IC. Thus, inducing CD4 T cell recall represents a novel therapeutic opportunity, with a distinct mode of inflammatory and antitumor potential. We hypothesize that intratumor childhood vaccine-specific CD4+ T cell recall responses instigate distinct and durable inflammatory reprograming of myeloid cells to potentiate antitumor CD8+ T cell function and mediate antitumor efficacy. To test this hypothesis, we will define reprogramming of innate immunity after triggering intratumor recall responses and determine its role in mediating antitumor efficacy (Aim 1) and test if polio vaccine-specific CD4+ T cell recall responses `help' antitumor CD8+ T cells (Aim 2). These analyses will inform clinically actionable routes to develop recall antigen-based therapies that enlist CD4 T cell help within tumors (the goal of the independent, R00 phase). The clinical translation of these findings will be informed by identifying therapeutic strategies, such as combined innate pattern recognition receptor agonist therapy, that may synergize with recall antigens in mediating systemic antitumor efficacy; as well as identifying more targeted molecular routes to recapitulate CD4 T cell help in tumors therapeutically (Aim 3). The K99 phase of this work will be mentored by several distinguished experts in tumor immunobiology and cancer immunotherapy: including Drs. Darell Bigner (primary Mentor, cancer immunotherapy of brain tumors), Simon Gregory (computational expert), Qi Jing-Li (T cell biologist using transcriptome analyses to gauge T cell function), Amy Heimberger (tumor associated myeloid cell expert who has previously applied transcriptome analyses to define activation/suppressive features of tumor associated myeloid cells), and James Herndon II (biostatistical support). This proposal will enable clinical translation of recall antigens to cancer patients and will seed a research program that leverages the potent immune-stimulating effects of CD4+ T cell help to develop novel cancer therapies.