(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:
- 金额:$ 41.74万
- 依托单位:
- 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:
- 关键词:AIDS related cancerAdaptive Immune SystemAdultAfricaAfrica South of the SaharaAftercareAntitumor ResponseBiologyCD8-Positive T-LymphocytesCD8B1 geneCTLA4 geneCancer EtiologyCellsCessation of lifeCharacteristicsClinicalClone CellsCytomegalovirusDevelopmentEpidemicFailureGene ExpressionGenesGenetic TranscriptionGoalsHIVHIV InfectionsHIV SeronegativityHigh-Throughput Nucleotide SequencingHuman Herpesvirus 4Human Herpesvirus 8ImmuneImmune System DiseasesImmune responseImmune systemImmunohistochemistryImmunologic Deficiency SyndromesIn complete remissionIndividualInstitutesKaposi SarcomaLearningLocationMalignant NeoplasmsMediatingMolecular ProfilingMorbidity - disease rateOutcomeParticipantPatientsPersonsPlayPopulationPrognostic FactorProspective cohort studyReceptors, Antigen, B-CellRefractoryRoleSamplingSkinSolidSolid NeoplasmStagingT cell clonalityT cell responseT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTestingTherapeuticTreatment outcomeTumor ExpansionTumor ImmunityTumor-Infiltrating LymphocytesTumor-infiltrating immune cellsUgandaVaccine TherapyViralVirusadaptive immune responseantiretroviral therapybasecheckpoint inhibitionchemotherapycohortdensityexhaustionfollow-upimmune checkpoint blockadeimmune functionimmune reconstitutionimmunogenic cell deathimprovedinsightmortalityneoplastic cellnovelpatient subsetsprogrammed cell death protein 1repositoryresponserestorationspatiotemporalsuccesssurvival outcometranscriptome sequencingtreatment responsetreatment strategytumortumor 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Warren Phipps其他文献
Warren Phipps的其他文献
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{{ truncateString('Warren Phipps', 18)}}的其他基金
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
- 批准号:
10400022 - 财政年份:2019
- 资助金额:
$ 41.74万 - 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
- 批准号:
10647642 - 财政年份:2019
- 资助金额:
$ 41.74万 - 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
- 批准号:
9759709 - 财政年份:2019
- 资助金额:
$ 41.74万 - 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
- 批准号:
10601276 - 财政年份:2019
- 资助金额:
$ 41.74万 - 项目类别:
(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
- 批准号:
10603060 - 财政年份:2017
- 资助金额:
$ 41.74万 - 项目类别:
Expanding independent research capacity in HIV-associated malignancies in Uganda
扩大乌干达艾滋病毒相关恶性肿瘤的独立研究能力
- 批准号:
9252603 - 财政年份:2014
- 资助金额:
$ 41.74万 - 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
- 批准号:
8312503 - 财政年份:2011
- 资助金额:
$ 41.74万 - 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
- 批准号:
8140721 - 财政年份:2011
- 资助金额:
$ 41.74万 - 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
- 批准号:
8700130 - 财政年份:2011
- 资助金额:
$ 41.74万 - 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
- 批准号:
8512671 - 财政年份:2011
- 资助金额:
$ 41.74万 - 项目类别:
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