Use of focused ultrasound to increase melanoma immunogenicity and inhibit tumor-induced T cell tolerance
Use of focused ultrasound to increase melanoma immunogenicity and inhibit tumor-induced T cell tolerance
批准号:
9893711
负责人:
Chandan Guha
金额:
$38.2万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-01 至 2023-03-31
关键词:
Adaptive Immune SystemAddressAdverse effectsAdverse reactionsAgonistAntibodiesAntigen-Presenting CellsAntigensAntitumor ResponseAutologousAutophagocytosisBehaviorCCL4 geneCTLA4 geneCancer VaccinesCarcinoma in SituCell DeathCell MaturationCell surfaceCellular StressClinicDataDendritic CellsDendritic cell activationDistalEGR2 geneFocused UltrasoundFocused Ultrasound TherapyGenerationsGoalsImmuneImmune ToleranceImmune checkpoint inhibitorImmune responseImmunotherapeutic agentImmunotherapyIn SituIn VitroMelanoma CellMelanoma VaccineMetastatic Neoplasm to the LungModelingMolecular ChaperonesMonitorMusNeoplasm MetastasisPathway interactionsPopulationPrecancerous melanosisPrimary NeoplasmProtocols documentationRecurrenceSpecificityStressSuppressor-Effector T-LymphocytesT cell responseT-Cell ActivationT-LymphocyteTherapeutic AgentsTimeToxic effectTranslatingTumor AntigensUltrasonic Therapyanti-melanoma immunityantigen-specific T cellscancer immunotherapycombinatorialcost effectivecytokinedesignexosomeimmune checkpoint blockadeimmunogenicimmunogenic cell deathimmunogenicityimmunoregulationimprovedin vivomelanomamouse modelneoplasm immunotherapyneoplastic cellnovelnovel therapeutic interventionpreventprogrammed cell death ligand 1programmed cell death protein 1programsrecruitresponsetranscription factortumortumor growthtumor microenvironmenttumor-immune system interactions
中文摘要
肿瘤微环境中的免疫抑制机制通过阻止肿瘤生长促进肿瘤生长
适应性免疫系统不会产生有效的抗肿瘤反应。经济衰退的主要后果之一是
免疫抑制的肿瘤微环境是诱导肿瘤抗原特异性T细胞耐受的机制。
克服这种障碍仍然是癌症免疫治疗中的一大挑战。我们的数据显示
低强度聚焦超声(LOFU)引起的热应激和物理应激可预防肿瘤的诱发
抗原特异性T细胞耐受性,并与消融治疗相结合,结果改善了对初发
黑色素瘤,减少局部复发,并显著减少肺转移的发生。这
代表了一种新的治疗方法,通过局部作用于肿瘤细胞,有可能抑制
肿瘤抗原特异性诱导T细胞耐受模型的建立在本应用程序中,我们的目标是了解
LOFU治疗后诱导免疫原性黑色素瘤细胞死亡的机制决定了
LOFU消融作为原位黑色素瘤疫苗的可能性及最终研究LOFU能否增加
与检查点抑制剂联合使用时,可提高效率并降低毒性。
英文摘要
Immunosuppressive mechanisms in the tumor microenvironment promote tumor growth by preventing the
adaptive immune system from mounting effective antitumor responses. One of the main consequences of the
immunosuppressive tumor microenvironment is the induction of tumor antigen-specific T cell tolerance.
Overcoming such blockade has remained a major challenge in cancer immunotherapy. Our data show that
thermic and physical stress induced by low-intensity focused ultrasound (LOFU) prevents the induction of tumor-
antigen specific T cell tolerance and, in combination with ablative therapy, results in improved control of primary
melanoma, reduces local recurrence and markedly decreases the occurrence of pulmonary metastases. This
represents a new therapeutic approach that by acting locally on tumor cells has the potential to inhibit the
establishment of tumor-antigen specific induced T cell tolerance. In this application, our goal is to understand
the mechanisms that induce enhanced immunogenic melanoma cell death after LOFU-treatment, determine the
potential of using LOFU+ablation as an in-situ melanoma vaccine and finally study whether LOFU can increase
efficiency and reduced toxicity when used in combination with checkpoint inhibitors.
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