权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

(PQ5) Effect of HIV infection on viral and host gene expression and antitumor immunity in Kaposi Sarcoma in Africa

(PQ5) HIV感染对非洲卡波西肉瘤病毒和宿主基因表达以及抗肿瘤免疫的影响

基本信息

批准号：
10603060
负责人：
Warren Phipps
金额：
$ 19.08万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-11 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603060
关键词：
PQ5 Effect HIV infection viral

项目摘要

ABSTRACT/PROJECT SUMMARY Kaposi sarcoma (KS) is among the most common HIV-associated malignancies worldwide, and a leading cause of cancer morbidity and mortality in sub-Saharan Africa. A growing body of evidence demonstrates the tremendous ability of T-cells to mediate tumor regression, and several characteristics of tumor-infiltrating lymphocytes (TIL) are associated with superior survival in a range of solid tumors. While KS development is strongly associated with immune dysfunction in the context of HIV infection, little is known about immune responses to KS, and no studies have evaluated features of TIL in KS tumors in relation to clinical outcomes. In response to PQ5, we propose the first study to define the characteristics of effective T-cell responses to KS in adults with and without HIV infection. Preliminary studies by our group demonstrate that T-cells commonly infiltrate HIV+KS tumors, and that higher T-cell receptor (TCR) clonality in tumor-infiltrating lymphocytes (TIL) is associated with improved treatment response. We have further observed the expansion of specific T-cell clones in post-treatment TIL in patients who ultimately achieve a complete response to therapy, and we hypothesize that these clones are reactive with KS tumor cells and contribute to tumor regression. Importantly, we have also found high expression in KS tumors of several immune exhaustion markers, including PD-1,CTLA-4, and LAG-3, which may be increased in HIV-infected individuals, and contribute to their inability to mount effective KS immune responses. By comparing TIL in HIV+ and HIV-KS tumors, we hope to learn about the impact of HIV on T-cell responses. We further postulate that persons with HIV-KS, who have no known immunodeficiency and typically enjoy superior treatment outcomes, will generate more effective antitumor responses that can guide therapeutic strategies to enhance similar T-cell responses in HIV+KS. We will test our hypotheses by utilizing the extensive KS tumor repository from our ongoing study of adults with HIV+KS and HIV-KS receiving treatment at the Uganda Cancer Institute through the following aims: 1) To define the spatiotemporal characteristics of TIL in KS tumors, and to determine if features of intratumoral CD4+ and CD8+ T-cell infiltration are associated with response to therapy and with 1-year survival. 2) To evaluate the diversity and clonal composition of the T-cell receptor β chain (TRB) repertoire of TIL in KS tumors, and to determine if clonal composition and/or specific clonal populations in TIL are correlated with response to therapy and 1-year survival. 3) To define the expression of viral and immune-related host genes in KS tumors, and to identify features associated with response to therapy and 1-year survival. Through an improved understanding of adaptive immune responses to KS, these studies will contribute to the development of targeted and effective immune-based staging and treatment strategies, including immune checkpoint inhibition and therapeutic vaccination, to improve response and survival in persons with HIV+KS.

摘要/项目总结卡波西肉瘤（KS）是世界上最常见的HIV相关恶性肿瘤之一，也是一种主要的是撒哈拉以南非洲地区癌症发病率和死亡率的主要原因。越来越多的证据表明， T细胞介导肿瘤消退的巨大能力，以及肿瘤浸润的几个特征，淋巴细胞（TIL）与一系列实体瘤中的上级存活相关。虽然KS的发展是与HIV感染背景下的免疫功能障碍密切相关，但对免疫功能障碍知之甚少。没有研究评估KS肿瘤中TIL的特征与临床结果的关系。为了响应PQ 5，我们提出了第一项研究，以确定有效的T细胞反应的特征，有和没有艾滋病毒感染的成年人的KS。我们小组的初步研究表明，通常浸润HIV+KS肿瘤，并且在肿瘤浸润中具有较高的T细胞受体（TCR）克隆性，淋巴细胞（TIL）的增加与改善的治疗反应相关。我们进一步观察到，在最终实现对治疗的完全应答的患者中治疗后TIL中的特异性T细胞克隆，我们假设这些克隆与KS肿瘤细胞反应并有助于肿瘤消退。重要的是，我们还发现KS肿瘤中几种免疫耗竭标志物的高表达，包括PD-1、CTLA-4和LAG-3，它们可能在HIV感染者中增加，并有助于其不能产生有效的KS免疫反应。通过比较HIV+和HIV-KS肿瘤中的TIL，我们希望了解艾滋病毒对T细胞反应的影响。我们进一步假设，患有HIV-KS的人，没有已知的免疫缺陷，通常享有上级治疗结果，将产生更有效的抗肿瘤反应，可以指导治疗策略，以增强类似的T细胞反应，在HIV+KS。我们将利用我们正在进行的成人研究中的广泛KS肿瘤库来验证我们的假设艾滋病毒携带者和艾滋病毒携带者在乌干达癌症研究所接受治疗，目的如下： 1)明确KS肿瘤中TIL的时空特征，并确定肿瘤内TIL的特征是否与肿瘤的病理特征有关。 CD 4+和CD 8 + T细胞浸润与治疗反应和1年生存率相关。 2)评估KS中TIL的T细胞受体β链（TRB）库的多样性和克隆组成肿瘤，并确定TIL中的克隆组成和/或特异性克隆群体是否与肿瘤的发生相关。对治疗有反应和1年生存率。 3)确定KS肿瘤中病毒和免疫相关宿主基因的表达，并确定特征与治疗反应和1年生存率相关。通过对KS适应性免疫反应的更好理解，这些研究将有助于制定有针对性和有效的基于免疫的分期和治疗策略，包括免疫检查点抑制和治疗性疫苗接种，以改善HIV+KS患者的反应和存活率。