Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
基本信息
- 批准号:10586476
- 负责人:
- 金额:$ 49.84万
- 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:2017-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:Alcohol consumptionAutomobile DrivingB-LymphocytesBiological MarkersBlood CirculationBone MarrowCD8-Positive T-LymphocytesCancer EtiologyCessation of lifeChemotherapy and/or radiationClinical TrialsCountryDeveloping CountriesDiseaseDisease OutcomeElementsFundingGenetic TranscriptionHead and Neck CancerHead and Neck NeoplasmsHead and Neck Squamous Cell CarcinomaHealthcareHuman PapillomavirusHuman papilloma virus infectionImmuneImmune checkpoint inhibitorImmunologic MarkersImmunosuppressionImmunotherapeutic agentImmunotherapyIncidenceInflammatoryInnate Immune ResponseInterleukin-10Interleukin-12Malignant NeoplasmsMediatingMolecularMorbidity - disease rateMusMyeloid CellsNatural Killer CellsOperative Surgical ProceduresPD-1 inhibitorsPathway interactionsPatient MonitoringPatient SelectionPatient-Focused OutcomesPatientsPhasePhase II Clinical TrialsPhenotypePhosphatidylinositol 4,5-DiphosphatePhosphotransferasesPlayProtein IsoformsProto-Oncogene Protein c-kitQuality of lifeRadiation therapyRegimenResistanceRoleSignal TransductionSurvival RateT cell responseT memory cellT-LymphocyteTestingTherapeuticTherapeutic AgentsTissuesTobacco useTumor ImmunityTumor-associated macrophagesUnited StatesWomanantagonistanti-PD-1anti-tumor immune responsearginasecytotoxiccytotoxic CD8 T cellsimprovedinhibitor therapymacrophagemalignant oropharynx neoplasmmenmortalitynovelnovel therapeutic interventionnovel therapeuticspatient biomarkersrecruitresponse biomarkersecondary lymphoid organtargeted agenttherapy outcometooltraffickingtreatment strategytumortumor eradicationtumor growthtumor microenvironmenttumor progression
项目摘要
Immune therapy holds great promise to improve disease outcomes for head and neck squamous cell carcinoma
(HNSCC) patients. The sixth most common cancer worldwide, HNSCC is a deadly and disfiguring disease that
accounted for more than 54,000 cases and 10,850 deaths in 2021 in the United States alone. Cases continue
to rise, in part due to increases in human papillomavirus (HPV) associated oropharynx cancers. The current
standard therapeutic regimens of surgery, chemotherapy and radiation therapy are associated with significant
morbidity and loss of quality of life with only modest 5-year survival rates. Immune therapy has offered new
options for HNSCC patients; treatment with T cell checkpoint inhibitors has led to gains in survival for 20-30% of
treated patients. However, the majority of HNSCC patients are resistant to T cell checkpoint inhibitors. Improved
therapeutic approaches that target additional mechanisms of immune escape are needed for this disease. Our
studies show that immune suppressive Tumor Associated Macrophages (TAMs) promote HNSCC immune
escape. We discovered that both tissue resident macrophages (TRM) and bone marrow derived macrophages
(BMDM) accumulate in HPV+ and HPV- HNSCC tumors, where they play distinct roles in promoting immune
suppression but also offer distinct vulnerabilities that can be targeted to promote tumor eradication. Targeting
proliferation pathways suppressed TRM accumulation and tumor progression while targeting the myeloid cell
specific phosphatidylinositol-4,5-bisphosphate 3-kinase isoform gamma (PI3Kg) suppressed BMDM
accumulation. Furthermore, PI3Kg inhibition promoted pro-inflammatory macrophage polarization that
synergized with checkpoint inhibitors to enhance recruitment and activation of cytotoxic CD8+ T cells, leading to
tumor eradication. These results indicated that therapeutic strategies that target TAMs as well as T cell
checkpoints could improve HNSCC patient outcomes. Biomarker studies in clinical trials showed that PI3Kg
antagonism stimulated enhanced T cell recruitment and activation in HNSCC patients. Therefore, we propose to
test the overall hypothesis that therapeutic strategies that block macrophage accumulation and immune
suppression will improve therapeutic outcomes in HNSCC disease. The specific aims of this proposal are: 1) To
identify and target mechanisms controlling macrophage accumulation in HNSCC tumors. 2) To determine how
macrophage plasticity can be harnessed to inhibit HNSCC tumor progression. 3) To develop novel immune
therapeutic strategies and immune biomarkers for HNSCC disease.
免疫疗法有望改善头颈部鳞状细胞癌的预后
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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Judith A VARNER其他文献
Judith A VARNER的其他文献
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{{ truncateString('Judith A VARNER', 18)}}的其他基金
10X Chromium Connect for Single Cell Library Preparations for Translational Research
用于转化研究的单细胞文库制备的 10X Chromium Connect
- 批准号:
10430292 - 财政年份:2022
- 资助金额:
$ 49.84万 - 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
- 批准号:
9763352 - 财政年份:2017
- 资助金额:
$ 49.84万 - 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
- 批准号:
9980195 - 财政年份:2017
- 资助金额:
$ 49.84万 - 项目类别:
Targeting the innate immune response in HNSCC
针对 HNSCC 的先天免疫反应
- 批准号:
10216217 - 财政年份:2017
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase in Tumor Progression and Metastasis
PI3激酶在肿瘤进展和转移中的作用
- 批准号:
10375512 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
- 批准号:
8828127 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
- 批准号:
8844128 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase in Tumor Progression and Metastasis
PI3激酶在肿瘤进展和转移中的作用
- 批准号:
10116294 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
- 批准号:
9516087 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
Role of PI3Kinase Gamma in Tumor Progression and Metastasis
PI3激酶γ在肿瘤进展和转移中的作用
- 批准号:
9033872 - 财政年份:2012
- 资助金额:
$ 49.84万 - 项目类别:
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