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，但癌症免疫治疗成功 仅限于一部分癌症类型。常规的CD 4或“辅助”T细胞在免疫调节中起着不可或缺的作用。 协调免疫应答，并且可以增强抗肿瘤免疫的功能：通过激活和 增强抗原呈递细胞功能和抗肿瘤CD 8 T细胞。我的博士后工作证明了 在瘤内注射回忆抗原（如脊髓灰质炎）后， 衣壳或破伤风类毒素），介导抗肿瘤功效，并引起体内先天性和适应性炎症。 肿瘤的肿瘤内回忆应答的抗肿瘤疗效部分依赖于CD 8 T细胞， 与活化的粒细胞巨噬细胞浸润一致，其表型不同于肿瘤相关的 用Poly IC直接先天刺激后的巨噬细胞。因此，诱导CD 4 T细胞回忆代表了一种新的 治疗机会，具有独特的炎症和抗肿瘤潜力模式。我们假设 肿瘤内儿童疫苗特异性CD 4 + T细胞回忆反应引发独特和持久的炎症反应 重新编程骨髓细胞以增强抗肿瘤CD 8 + T细胞功能并介导抗肿瘤功效。到 为了验证这一假设，我们将定义在触发肿瘤内回忆反应后先天免疫的重编程 并确定其在介导抗肿瘤疗效中的作用（目标1），并测试脊髓灰质炎疫苗特异性CD 4 + T细胞回忆是否 应答“帮助”抗肿瘤CD 8 + T细胞（Aim 2）。这些分析将为临床可行的开发路线提供信息 回顾基于抗原的疗法，在肿瘤内招募CD 4 T细胞的帮助（独立的，R 00阶段的目标）。 这些发现的临床翻译将通过确定治疗策略，如联合 先天模式识别受体激动剂疗法，其可与回忆抗原协同介导全身性 抗肿瘤疗效;以及确定更具针对性的分子途径，以重现CD 4 T细胞在肿瘤中的帮助 治疗（目标3）。这项工作的K99阶段将由几位杰出的肿瘤专家指导 免疫生物学和癌症免疫疗法：包括Darell Bigner博士（主要导师，癌症免疫疗法 Simon Gregory（计算专家），Qi Jing-Li（使用转录组分析的T细胞生物学家 测量T细胞功能），Amy Heimberger（肿瘤相关骨髓细胞专家， 转录组分析以确定肿瘤相关骨髓细胞的活化/抑制特征），以及James Herndon II（生物统计支持）。这一提议将使召回抗原的临床翻译成为可能 患者，并将种子的研究计划，利用强大的免疫刺激作用的CD 4 + T细胞 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.