Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing.
Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing.
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DOI：
10.3389/fonc.2020.589434
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发表时间：
2020
影响因子：
4.7
通讯作者：
Mendler AN
中科院分区：
文献类型：
--
作者：
Fischbeck AJ;Ruehland S;Ettinger A;Paetzold K;Masouris I;Noessner E;Mendler AN
过继T细胞疗法(ACT)在血液系统恶性肿瘤的治疗中非常有效，但在实体瘤中的疗效有限。肿瘤环境中T细胞的失活是ACT广泛应用的主要障碍。细胞毒性是与肿瘤根除最相关的活性。在此，我们发现乳酸中毒患者的细胞毒性T细胞(CTL)对肿瘤细胞的杀伤作用显著降低，这可以通过增加CTL与肿瘤细胞的比例来部分补偿。乳酸在杀死过程的多个步骤中起到了干预作用。乳酸抑制了在肿瘤细胞共培养中执行裂解颗粒排出(脱颗粒)的CTL的数量，此外，还损害了反应的质量，从脱颗粒的强度和细胞毒素(穿孔素、颗粒酶B、颗粒酶A)的分泌减少来判断。乳酸中的CTL转变为低生物能谱，不能有效代谢葡萄糖。它们对抗CD3刺激的反应较差，胞外酸化率(ECAR)较低。这可能解释了它们被抑制的颗粒胞吐活性。利用活细胞成像，我们发现乳酸中的CTL活力降低，导致视野覆盖率降低。乳酸酸中毒时，许多CTL不与肿瘤细胞接触，但与肿瘤细胞接触的时间比正常介质中的CTL长得多。活动减少和接触时间延长阻碍了连环杀戮，这是杀伤力的一个定义特征，但也局部限制了细胞毒活动，这有助于降低附带器官损伤的风险。这些活动将乳酸定义为一种主要的信号分子，能够协调炎症组织(如癌症)中CTL的空间分布，并减缓其功能反应。乳酸干预和改善T细胞代谢适合性的策略有望提高基于T细胞的癌症免疫治疗的临床疗效。
Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy.
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影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
2.2
作者：
Devevre, Estelle;Romero, Pedro;Mahnke, Yolanda D.
通讯作者：
Mahnke, Yolanda D.
影响因子：
9.8
作者：
Haas R;Smith J;Rocher-Ros V;Nadkarni S;Montero-Melendez T;D'Acquisto F;Bland EJ;Bombardieri M;Pitzalis C;Perretti M;Marelli-Berg FM;Mauro C
通讯作者：
Mauro C
影响因子：
11.1
作者：
Hartmann J;Schüßler-Lenz M;Bondanza A;Buchholz CJ
通讯作者：
Buchholz CJ
影响因子：
64.5
作者：
Buck MD;Sowell RT;Kaech SM;Pearce EL
通讯作者：
Pearce EL