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个子集。传统的 CD4 或“辅助”T 细胞在 协调免疫反应，并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 CD8 T 细胞。我的博士后工作证明 肿瘤内注射回忆抗原后重新激活儿童疫苗特异性 CD4 T 细胞（例如脊髓灰质炎） 衣壳或破伤风类毒素），介导抗肿瘤功效并引起先天性和适应性炎症 肿瘤。肿瘤内回忆反应的抗肿瘤功效部分依赖于 CD8 T 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同时发生 Poly IC 直接先天刺激后的巨噬细胞。因此，诱导 CD4 T 细胞召回代表了一种新的方法。 治疗机会，具有独特的炎症模式和抗肿瘤潜力。我们假设 肿瘤内儿童疫苗特异性 CD4 T 细胞回忆反应引发独特且持久的炎症 骨髓细胞重新编程以增强抗肿瘤 CD8 T 细胞功能并介导抗肿瘤功效。至 检验这个假设，我们将定义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功效中的作用（目标 1）并测试脊髓灰质炎疫苗特异性 CD4 T 细胞回忆是否有效 反应“帮助”抗肿瘤 CD8 T 细胞（目标 2）。这些分析将为临床可行的开发途径提供信息 回想一下基于抗原的疗法，该疗法在肿瘤内招募 CD4 T 细胞帮助（独立 R00 阶段的目标）。 这些发现的临床转化将通过确定治疗策略来告知，例如联合治疗 先天模式识别受体激动剂疗法，可能与回忆抗原协同介导全身性 抗肿瘤功效；以及确定更有针对性的分子途径来概括 CD4 T 细胞对肿瘤的帮助 治疗（目标 3）。这项工作的K99阶段将由多位肿瘤领域杰出专家指导 免疫生物学和癌症免疫治疗：包括博士。 Darell Bigner（主要导师，癌症免疫疗法 脑肿瘤）、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，之前曾申请 转录组分析以确定肿瘤相关骨髓细胞的激活/抑制特征），和 James Herndon II（生物统计支持）。该提案将使记忆抗原临床转化为癌症 患者并将启动一项研究计划，利用 CD4 T 细胞的强大免疫刺激作用 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.