Immune Checkpoints and HPV-associated Head and Neck Cancers

 描述(申请人提供)：免疫检查点阻断在治疗转移性和/或局部复发黑色素瘤患者方面取得了巨大成功，这促使人们越来越努力地研究将这一策略应用于其他实体肿瘤。病毒相关性实体瘤是评估免疫耐药机制的理想选择，因为与外来高免疫原性病毒抗原的局部表达相关的固有炎症。HPV相关性头颈部鳞状细胞癌(HPV-HNSCC)起源于扁桃体，扁桃体是协调免疫对抗口腔感染的主要淋巴器官。尽管它的 位于淋巴丰富的环境中，HPV在恶性转化和进展过程中逃避免疫消除。我们的团队最近发现，免疫检查点途径，程序性细胞死亡-1(PD-1)和程序性细胞死亡1配体-1(PD-L1)，促进了持续的病毒感染和随后的癌症发展。我们的发现支持PD-1：PD-L1途径被诱导为针对宿主肿瘤的适应性免疫抵抗机制的模型。我们使用包含59个免疫相关基因的定制微阵列，进一步研究了激活PD-1：PD-L1免疫检查点通路的HPV-HNSCCs的免疫特征。我们发现IL-10和IDO1是PD-L1表达免疫前沿上调最多的两个基因。有趣的是，这两种基因都能抑制宿主免疫反应，而且都是药物的靶点。基于这些发现，我们建议测试在HPV-HNSCC中阻断IL-10和/或IDO1通路是否可以增强宿主抗肿瘤免疫反应。我们建议首先使用定量聚合酶链式反应和多重生物标记物成像和定量分析来量化和地理定位这些蛋白在单独的HPV-HNSCC患者队列中的表达。随后，我们将在小鼠HPV肿瘤模型中评估单独或联合抗PD1阻断IL10和/或IDO1通路的有效性。然后，我们建议将这些标记物的表达与头颈癌患者抗PD-1单一治疗的临床反应相关联。我们假设这些基因的表达可以作为预测生物标志物和/或适应性抵抗PD-1阻断的途径。这一结果可能为未来临床试验中针对多个免疫检查点的新型组合疗法提供理论基础。这一建议与美国国立卫生研究院将肿瘤-宿主相互作用、肿瘤微环境和免疫检查点的分子特征作为高度优先研究领域的认识相一致。

 DESCRIPTION (provided by applicant): The dramatic success of immune checkpoint blockade in treating patients with metastatic and/or locally recurrent melanoma has stimulated increasing efforts to investigate the application of this strategy to other solid tumors. Virus-associated solid tumors are ideal for evaluating immune resistance mechanisms, given the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. HPV-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsil, the major lymphoid organ that orchestrates immunity against oral infection. Despite its location in a lymphoid-rich environment, HPV escapes immune elimination during malignant transformation and progression. Our group recently showed that the immune checkpoint pathway, Programmed Cell Death-1 (PD-1) and Programmed Cell Death 1 Ligand-1 (PD-L1), facilitates persistent viral infection and subsequent development of cancer. Our findings support a model in which the PD-1:PD-L1 pathway becomes induced as an adaptive immune-resistance mechanism against the host tumor. We further investigated the immune signature of HPV-HNSCCs with activation of the PD-1:PD-L1 immune checkpoint pathway using a custom microarray with 59 immune-related genes. We found that IL-10 and IDO1 were the top two genes upregulated in PD-L1 expressing immune fronts. Interestingly, both of these genes are known to suppress host immune responses and both are targetable by drugs. Based on these findings, we propose to test whether blocking IL-10 and/or IDO1 pathways in HPV-HNSCC can enhance host anti-tumor immune responses. We propose to first quantify and geographically localize the expression of these proteins in a separate cohort of HPV-HNSCC patients using quantitative PCR and multiplex biomarker imaging and quantitative analysis. Subsequently, we will assess the efficacy of blocking in vivo either the IL10 and/or IDO1 pathway alone or in combination with anti-PD1 in a murine HPV tumor model. We then propose to correlate expression of these markers with clinical response to anti-PD-1 monotherapy in head and neck cancer patients. We hypothesize that expression of these genes can serve as a predictive biomarker and/or pathway of adaptive resistance to PD-1 blockade. The results may provide rationale for novel combinatorial therapies which target multiple immune checkpoints in future clinical trials. This proposal is in alignment with the NIH recognition of molecular signatures of tumor-host interactions, tumor microenvironments, and immune checkpoints as high priority areas of research.