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

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是最具免疫抑制作用的人类肿瘤之一。肿瘤诱导和治疗诱导的免疫抑制可能是接受根治性治疗的SCCHN患者中超过60%的疾病复发的原因。我们的数据表明，腺苷和PGE2是HNSCC的主要免疫抑制因子。不仅肿瘤而且调节性T细胞(Treg)也会产生这些因子，在肿瘤进展过程中，适应性Treg会在肿瘤微环境中积累。在化疗(CRT)后，它们的频率和功能增加，并在几个月内保持升高，可能导致肿瘤复发。在这项建议中，我们检验了这样一个假设，即在 通过以腺苷/前列腺素E_2途径为靶点的药物下调Treg和增强T效应细胞功能，可以在体外和体内实现HNSCC的微环境。基于三个目标，我们建议：(1)在接受手术和CRT治疗的HNSCC患者中进行前瞻性的非治疗性纵向研究，以探讨CRT后持续免疫抑制和腺苷/PGE2途径活性增强是否与肿瘤复发有关；(2)体外研究药物阻断腺苷/PGE2途径对Treg介导的抑制和潜在伴随的Tef抗肿瘤功能恢复的影响；(3)体内腺苷酸环化酶的代谢沉默和磷酸二酯酶活性的刺激促进了对多表位疫苗的抗肿瘤免疫应答，诱导了肿瘤排斥反应，延长了4NQO口腔癌小鼠的生存时间。这些临床前研究旨在证明，Treg在人类肿瘤微环境中的持续积聚与肿瘤的进展有关，而单独或与传统癌症治疗结合使用对常见免疫抑制途径的药理阻断可以沉默Treg，恢复抗肿瘤免疫并抑制肿瘤生长。这种新的联合疗法在HNSCC患者CRT后重建有效抗肿瘤免疫的潜力有望为其临床应用提供理论基础。

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.