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(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：
9903247
负责人：
Warren Phipps
金额：
$ 41.74万
依托单位：
FRED HUTCHINSON CANCER RESEARCH 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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903247
关键词：
AIDS related cancer Adaptive Immune System Adult Africa Africa South of the Sahara Aftercare Antitumor Response Biology CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cancer Etiology Cells Cessation of life Characteristics Clinical Clone Cells Cytomegalovirus Development Epidemic Failure Gene Expression Genes Genetic Transcription Goals HIV HIV Infections HIV Seronegativity High-Throughput Nucleotide Sequencing Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune System Diseases Immune response Immune system Immunohistochemistry Immunologic Deficiency Syndromes In complete remission Individual Institutes Kaposi Sarcoma Learning Location Malignant Neoplasms Mediating Molecular Profiling Morbidity - disease rate Outcome Participant Patients Persons Play Population Prognostic Factor Prospective cohort study Receptors, Antigen, B-Cell Refractory Role Sampling Skin Solid Solid Neoplasm Staging T cell clonality T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Treatment outcome Tumor Expansion Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Uganda Vaccine Therapy Viral Virus adaptive immune response antiretroviral therapy base checkpoint inhibition chemotherapy cohort density exhaustion follow-up immune checkpoint blockade immune function immune reconstitution immunogenic cell death improved insight mortality neoplastic cell novel patient subsets programmed cell death protein 1 repository response restoration spatiotemporal success survival outcome transcriptome sequencing treatment response treatment strategy tumor tumor microenvironment

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.

抽象/项目总结