Chemokine-mediated antigen-specific T cell responses and immunotherapies to treat head and neck cancer

项目摘要 人乳头瘤病毒（HPV）与5%的人类癌症有因果关系，包括几乎所有的宫颈癌。 癌症和~25%的头颈部鳞状细胞癌（HNSCC），在很大程度上推动了持续流行 近几十年来HPV阳性（HPV+）HNSCC的增加。然而，人们对这些机制知之甚少， 由HPV驱动的疾病进展，特别是在宿主免疫的背景下。根据我们初步的 研究结果，我们将研究趋化因子CXCL 14抑制HNSCC生长的机制， CXCL 14是治疗HPV+ HNSCC的新型免疫疗法的有用免疫调节靶标。 最近，我们发现，恢复HPV+ HNSCC细胞中CXCL 14的抑制表达， 通过上调MHC-I抗原抑制免疫活性同系小鼠中的肿瘤生长 抗原呈递和抗原特异性CD 8 + T细胞应答。基于我们的发现，我们假设CXCL 14 通过增强抗原呈递诱导抑制HPV+ HNSCC的抗肿瘤免疫应答， CXCL 14能诱导CD 8 + T细胞应答，因此CXCL 14是一种潜在的新型免疫抑制剂。来测试我们 假设，我们将1）定义CXCL 14上调MHC-I抗原呈递的机制， 2）确定CXCL 14诱导CD 8 + T细胞增殖的机制 3）测试基于CXCL 14的免疫疗法，其诱导抗肿瘤细胞浸润/活化和肿瘤抑制;和 免疫和清除HPV+ HNSCC。我们的研究将为抗肿瘤免疫机制提供新的认识 HPV+ HNSCC的免疫防御，并可能导致HNSCC的新免疫疗法，特别是对非HPV + HNSCC的免疫治疗。 在当前的免疫疗法中。

PROJECT SUMMARY Human papillomaviruses (HPVs) are causally linked to 5% of all human cancers, including nearly all cervical cancers and ~25% of head and neck squamous cell carcinomas (HNSCCs), largely driving an ongoing epidemic increase of HPV-positive (HPV+) HNSCCs over recent decades. However, little is known about the mechanisms of disease progression driven by HPV, particularly in the context of host immunity. Based on our preliminary findings, we will study the mechanism by which the chemokine CXCL14 suppresses HNSCC growth, and test if CXCL14 serves as a useful immunomodulatory target for novel immunotherapies to treat HPV+ HNSCC. Recently, we have revealed that restoring the suppressed expression of CXCL14 in HPV+ HNSCC cells greatly suppressed tumor growth in immunocompetent syngeneic mice through upregulation of MHC-I antigen presentation and antigen-specific CD8+ T cells responses. Based on our findings, we hypothesize that CXCL14 induces antitumor immune responses that suppress HPV+ HNSCC by enhancing antigen presentation and eliciting CD8+ T cell responses, and thus CXCL14 is a potential novel immunotherapeutic agent. To test our hypothesis, we will 1) Define the mechanisms by which CXCL14 upregulates MHC-I antigen presentation to mediate tumor suppression; 2) Define the mechanisms by which CXCL14 induces CD8+ T cell infiltration/activation and tumor suppression; and 3) Test CXCL14-based immunotherapies that induce antitumor immunity and clear HPV+ HNSCC. Our study will provide new mechanistic understanding of antitumor immune defenses in HPV+ HNSCC and may lead to a novel immunotherapy for HNSCC, particularly for the non- responders in current immunotherapies.