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

摘要/项目摘要 卡波西肉瘤(KS)是世界上最常见的与艾滋病毒相关的恶性肿瘤之一，也是一种主要的 撒哈拉以南非洲癌症发病率和死亡率的原因。越来越多的证据表明 T细胞介导肿瘤消退的巨大能力和肿瘤浸润性的几个特征 淋巴细胞(TIL)在一系列实体肿瘤中与较高的存活率有关。而KS开发则是 在艾滋病毒感染的背景下，免疫功能障碍与免疫功能障碍密切相关，对免疫功能知之甚少 对KS的反应，没有研究评估KS肿瘤中TIL的特征与临床结果的关系。 作为对PQ5的回应，我们提出了第一项研究，以确定有效的T细胞对 感染和不感染HIV的成人中的KS。我们小组的初步研究表明，T细胞 通常浸润性HIV+KS肿瘤，肿瘤浸润性T细胞受体(TCR)克隆性较高 淋巴细胞(TIL)与改善治疗反应有关。我们进一步观察到， 最终对治疗完全有效的患者治疗后TIL中的特异性T细胞克隆， 我们假设这些克隆与KS肿瘤细胞有反应，并有助于肿瘤的消退。 重要的是，我们还发现几种免疫耗竭标志物在KS肿瘤中高表达， 包括PD-1、CTLA-4和LAG-3，它们在艾滋病毒感染者中可能会增加，并有助于他们的 无法进行有效的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，通常享有优越的治疗结果，将产生更有效的 抗肿瘤反应，可以指导治疗策略，以增强类似的艾滋病毒+KS的T细胞反应。 我们将利用我们正在进行的成人研究中的广泛的KS肿瘤存储库来测试我们的假设 通过下列目标在乌干达癌症研究所接受艾滋病毒+KS和艾滋病毒-KS治疗： 1)明确KS肿瘤中TIL的时空特征，并确定肿瘤内TIL的特征 CD_4~+和CD_8~+T细胞浸润与治疗反应和一年生存率有关。 2)研究KS患者TIL T细胞受体β链(Trb)的多样性和克隆性组成 肿瘤，并确定TIL中的克隆组成和/或特定克隆群是否相关 对治疗有反应，1年内存活。 3)明确病毒和免疫相关宿主基因在KS肿瘤中的表达，并确定其特征 与治疗反应和一年存活率有关。 通过更好地了解对KS的适应性免疫反应，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 检查站抑制和治疗性疫苗接种，以提高艾滋病毒+KS患者的反应和存活率。

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.