Restoring anti-tumor immunity in the microenvironment of head and neck cancer

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是免疫抑制性最强的人类肿瘤之一。肿瘤诱导和治疗诱导的免疫抑制可能是导致超过60%接受治愈性治疗的SCCHN患者疾病复发的原因。我们的数据表明，腺苷和PGE 2是HNSCC的主要免疫抑制因子。不仅肿瘤而且调节性T细胞（Treg）也产生这些因子，并且适应性Treg在肿瘤进展期间在肿瘤微环境中积累。它们的频率和功能在放化疗（CRT）后增加，并在数月内保持升高，可能导致肿瘤复发。在这个提议中，我们检验了这样一个假设，即在肿瘤细胞中恢复抗肿瘤免疫力是一个非常重要的因素。 HNSCC微环境的改善可以通过使用靶向腺苷/PGE 2途径的药理学试剂下调Treg和增强T效应细胞（Teff）功能在体外和体内实现。本研究的目的有三：（1）对接受手术和CRT治疗的HNSCC患者进行前瞻性非治疗性纵向研究，探讨CRT治疗后持续的免疫抑制和腺苷/PGE 2通路活性增强是否与肿瘤复发有关;（2）研究腺苷/PGE 2通路的药理学阻断对Treg-1的体外作用。介导的抑制和可能伴随的Teff抗肿瘤功能的恢复;和（3）显示Teff中腺苷酸环化酶的代谢沉默和磷酸二酯酶活性的刺激在体内促进对多表位疫苗的抗肿瘤免疫应答，诱导肿瘤排斥反应和口腔癌4 NQO小鼠的存活率。这些临床前研究旨在证明Treg在人肿瘤微环境中的持续积累与肿瘤进展相关，并且单独或与常规癌症治疗组合的常见免疫抑制途径的药理学阻断使Treg沉默，恢复抗肿瘤免疫并抑制肿瘤生长。这种新的组合疗法在HNSCC中CRT后重建有效抗肿瘤免疫的潜力有望为其转化为临床提供理论基础。

DESCRIPTION (provided by applicant): Squamous cell carcinomas of the head and neck (HNSCC) are among the most immunosuppressive human tumors. Tumor-induced and therapy-induced immune suppression may be responsible for disease recurrence seen in over 60% of SCCHN patients receiving curative therapies. Our data indicate that adenosine and PGE2 are among the major immunosuppressive factors in HNSCC. Not only the tumor but also regulatory T cells (Treg) produce these factors, and adaptive Treg accumulate in the tumor microenvironment during tumor progression. Their frequency and function increase after chemoradiation (CRT) and remain elevated for months, potentially contributing to tumor recurrence. In this proposal, we test the hypothesis that restoration of anti-tumor immunity in the microenvironment of HNSCC can be achieved in vitro and in vivo by down-regulating Treg and enhancing Teffector cell (Teff) functions using pharmacologic agents which target the adenosine/PGE2 pathway. In three aims, we propose to: (1) conduct a prospective non-therapeutic longitudinal study in HNSCC patients treated with surgery and CRT to ask whether persistent immune suppression and enhanced activity of the adenosine/PGE2 pathway after CRT contribute to the tumor recurrence; (2) study in vitro effects of the pharmacological blockade of the adenosine/PGE2 pathway on Treg-mediated suppression and potentially concomitant restoration of anti-tumor functions of Teff; and (3) show that metabolic silencing of the adenylyl cyclase and stimulation of phosphodiesterase activity in Teff in vivo promotes anti-tumor immune responses to a multi-epitope vaccine, induces tumor rejection and prolongs survival of 4NQO mice with oral carcinoma. These pre-clinical studies are designed to demonstrate that persistent accumulations of Treg in the human tumor microenvironment are associated with tumor progression and that the pharmacological blockade of a common immunosuppressive pathway alone or in combination with conventional cancer therapy silences Treg, restores anti-tumor immunity and inhibits tumor growth. The potential of this new combinatorial therapy for re-establishing effective anti-tumor immunity following CRT in HNSCC is expected to provide the rationale for its translation to the clinic.