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

项目总结 人类乳头瘤病毒(HPV)与5%的人类癌症有因果关系，包括几乎所有的宫颈癌 癌症和约25%的头颈部鳞状细胞癌(HNSCC)，在很大程度上推动了持续的流行 近几十年来，HPV阳性(HPV+)HNSCCs的数量有所增加。然而，人们对这种机制知之甚少。 人类乳头瘤病毒驱动的疾病进展，特别是在宿主免疫的背景下。根据我们的初步调查 我们将研究趋化因子CXCL14抑制HNSCC生长的机制，并测试 CXCL14为治疗HPV+HNSCC的新型免疫疗法提供了有用的免疫调节靶点。 最近，我们发现，在HPV+HNSCC细胞中，CXCL14的表达受到抑制后，可以在很大程度上恢复其表达 MHC-I抗原上调抑制免疫活性同基因小鼠肿瘤生长 呈递和抗原特异性CD8+T细胞反应。根据我们的发现，我们假设CXCL14 诱导抗肿瘤免疫反应，通过增强抗原提呈和抑制HPV+HNSCC 激发CD8+T细胞反应，因此CXCL14是一种潜在的新型免疫治疗剂。测试我们的 假设，我们将1)定义CXCL14上调MHC-I抗原递呈到 介导肿瘤抑制；2)确定CXCL14诱导CD8+T细胞的机制 3)检测基于CXCL14的诱导抗肿瘤的免疫疗法 免疫和清除HPV+HNSCC。我们的研究将为抗肿瘤免疫提供新的机制理解 HPV+HNSCC的防御作用，并可能导致HNSCC的一种新的免疫疗法，特别是对非 目前免疫疗法中的应答者。

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.