Systems Biology of Antigen and T-Cell Transport in Cancer Immunotherapy
癌症免疫治疗中抗原和 T 细胞运输的系统生物学
基本信息
- 批准号:10751192
- 负责人:
- 金额:$ 50.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAnatomyAnimal ExperimentsAnimal ModelAntibodiesAntigen-Presenting CellsAntigensAntitumor ResponseBiologyBiometryBlood CirculationBreast Cancer ModelCancer EtiologyCellsCirculationClinicalComplementComputer ModelsDataData SetDisseminated Malignant NeoplasmDrug KineticsEffectivenessEpitopesExcisionFailureGenerationsImmuneImmune EvasionImmune responseImmunologistImmunosuppressionImmunotherapyImpairmentLymphaticLymphatic SystemLymphatic functionLymphocyteLymphocyte ActivationMalignant NeoplasmsMeasurementMeasuresMechanicsMetastatic Neoplasm to Lymph NodesModelingMusNatureNeoplasm MetastasisNon-Small-Cell Lung CarcinomaPatientsPatternPhysiologicalPopulationProbabilityProcessPrognosisSamplingStochastic ProcessesSystems BiologyT memory cellT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTumor AntigensTumor ImmunityWorkanti-CTLA-4 therapyanti-PD-1anti-PD1 therapyanti-canceranti-tumor immune responseantigen-specific T cellscancer cellcancer immunotherapycancer therapychemokinecohortdraining lymph nodeexperimental studyfluid flowimmune activationimmune checkpointimmune checkpoint blockadeimmune checkpoint blockersimmune functionimmunoreactionimmunoregulationimprovedimproved outcomein vivoindividual patientinsightlymph flowlymph nodesmathematical modelmelanomamouse modelmulti-scale modelingmultidisciplinarypharmacodynamic modelpredicting responsepredictive markerpreventresidenceresponsestemtraffickingtumortumor growth
项目摘要
ABSTRACT
Cancer cells often exploit immune checkpoint molecules to suppress and evade immune responses;
by inhibiting this process, immune checkpoint blockers (ICBs) have transformed cancer treatment.
Unfortunately, ICB therapy only benefits <20% of patients, and there are no robust biomarkers for
predicting response in any individual patient. Recent data confirm that effective ICB responses require
activation of new T cells in lymph nodes. The T cell receptors on a given T cell are specific for certain
antigen epitopes, and only a small subset of naive T cells can recognize tumor antigens. Activation of
naïve T cells to initiate the anti-tumor response requires physical interaction with an antigen presenting
cell (APC) displaying the correct, specific cognate antigen recognized by that specific T cell. The co-
localization of the APC, naïve T-cell and cognate antigen is facilitated by the lymphatic system, which
can concentrate APCs and antigen in lymph nodes. However, due to the rich diversity of antigen
reactivity of the T cell population, there are limited numbers of T cells specific for any single antigen.
This fact, along with the random nature of T cell circulation and sampling of the many lymph nodes,
suggests that T cell activation depends on stochastic processes. Logically, the presence of more
antigen, or antigen in more lymph nodes should increase the probability of T-cell activation.
Furthermore, the trafficking and interaction of naïve T-cells and APCs can be disrupted by the presence
of metastatic cancer cells in the lymph node, which impairs anti-cancer immune responses and the
response to ICB. The proposed work analyzes how lymph node metastases impair the generation of
anti-cancer immune responses. We hypothesize that mechanical and physiological disruptions caused
by metastases can interfere with lymph flow, antigen transport and T cell trafficking in the lymph node,
and therefore directly affect anti-tumor immunity by reducing the probability of lymphocyte activation.
In this project, we will address this hypothesis using mechanistic, multiscale computational modeling to
identify specific reasons for the failure to initiate anti-tumor immunity. Our computational model will be
supported by our unique, state-of-the-art animal models to measure immune cell trafficking, lymphatic
function and tumor growth in various conditions. Once validated, the computational model will provide
a mechanistic framework for selecting additional treatments to increase lymphocyte activation and thus
the response rate to immunotherapy. We have assembled a team of leading computational modelers,
lymphatic biologists, immunologists and cancer biologists. This multidisciplinary team is supported by
expert collaborators in biostatistics, computational models of lymph nodes and measurements of lymph
flow in vivo. Together, the R01 team will gain critical insights into modes of failure of immune checkpoint
blockade and develop testable solutions to unleash anti-tumor immune responses for more patients
with cancer.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('LANCE L MUNN', 18)}}的其他基金
Targeting glycocalyx-mediated mechanisms of tumor metastasis
靶向糖萼介导的肿瘤转移机制
- 批准号:
10053711 - 财政年份:2016
- 资助金额:
$ 50.5万 - 项目类别:
Targeting glycocalyx-mediated mechanisms of tumor metastasis
靶向糖萼介导的肿瘤转移机制
- 批准号:
9238929 - 财政年份:2016
- 资助金额:
$ 50.5万 - 项目类别:
Encouraging anastomosis of engrafted vascular networks
促进移植血管网络的吻合
- 批准号:
8440749 - 财政年份:2012
- 资助金额:
$ 50.5万 - 项目类别:
Encouraging anastomosis of engrafted vascular networks
促进移植血管网络的吻合
- 批准号:
8236426 - 财政年份:2012
- 资助金额:
$ 50.5万 - 项目类别:
Encouraging anastomosis of engrafted vascular networks
促进移植血管网络的吻合
- 批准号:
8618916 - 财政年份:2012
- 资助金额:
$ 50.5万 - 项目类别:
Encouraging anastomosis of engrafted vascular networks
促进移植血管网络的吻合
- 批准号:
8821655 - 财政年份:2012
- 资助金额:
$ 50.5万 - 项目类别:
Flow-based remodeling and function of tumor vasculature
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8064674 - 财政年份:2010
- 资助金额:
$ 50.5万 - 项目类别:
Flow-based remodeling and function of tumor vasculature
基于流的肿瘤脉管系统重塑和功能
- 批准号:
8460445 - 财政年份:2010
- 资助金额:
$ 50.5万 - 项目类别:
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