キラーＴ細胞のエネルギー代謝機構の解析とＰＤ－１阻害がん免疫治療の効果予測

杀伤T细胞能量代谢机制分析及PD-1抑制癌症免疫治疗疗效预测

• 批准号: 18J15051
• 负责人: Kumar Alok
• 金额: $ 1.22万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2018
• 资助国家: 日本
• 起止时间: 2018-04-25 至 2020-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18J15051/
• 关键词: PD-1; Immunosupression; PGC-1alpha; Biomarker; Mitochondrial activation; biomarker; cancer immunotherapy

We classified unresponsiveness reasons into i). unresponsvieness because of local reasons ii). unresponsiveness because of having systemic immunosuppressive property (SIP). In addition, we found immune response after PD-1 blockade is associated with mitochondrial activation. Based on this result, we concluded that mitochondrial activation could be biomarker to identify responder and nonresponders. Further, we found SIP-positive tumors release non-proteinaceous small molecule that inhibit mitochondrial activation and proliferation of T cells. Bezafibrate when used alongwith culture superntant cancels the suppressive effect of supernatnat. Bezafibrate treatment alongwith PD-1 blockade enhances the survival of host bearing SIP-positive tumor compared to PD-1 blockade alone.

我们将无反应的原因分为i）。（二）因地方原因造成的不作为。由于具有全身性免疫抑制特性（SIP）而无反应性。此外，我们发现PD-1阻断后的免疫应答与线粒体活化相关。基于这一结果，我们得出结论，线粒体活化可能是识别应答者和无应答者的生物标志物。此外，我们发现SIP阳性肿瘤释放非蛋白质小分子，抑制线粒体激活和T细胞增殖。苯扎贝特与培养上清液一起使用时，可消除上清液的抑制作用。与单独的PD-1阻断剂相比，苯扎贝特治疗与PD-1阻断剂一起提高了携带SIP阳性肿瘤的宿主的存活率。

项目成果

Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

• DOI: 10.7554/elife.52330
• 发表时间: 2020-03-03
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Kumar, Alok;Chamoto, Kenji;Honjo, Tasuku
• 通讯作者: Honjo, Tasuku

Mechanistic analysis of unresponsiveness to the PD-1 blockade therapy

PD-1阻断治疗无反应的机制分析

• 发表时间: 2018
• 作者: Kumar;A.
• 通讯作者: A.

Inhibition of mitochondria by tumor-derived small molecule leads to systemic unresponsiveness to PD-1 blockade therapy

肿瘤源性小分子对线粒体的抑制导致全身对 PD-1 阻断疗法无反应

• 发表时间: 2019
• 作者: Alok Kumar;Kenji Chamoto;Tasuku Honjo
• 通讯作者: Tasuku Honjo

Bezafibrate enhances PD-1 blockade efficacy by activating mitochondrial biogenesis and effector function of CTLs

Bezafibrate 通过激活线粒体生物合成和 CTL 效应器功能来增强 PD-1 阻断功效

• 发表时间: 2018
• 作者: Kumar;A.
• 通讯作者: A.