放疗通过代谢产物乳酸调控微环境中MDSC从而影响肿瘤复发的机制研究

Radiotherapy plays an important role in the treatment of cancer. Although modern technology has made it an effective tool, there are still many life-threatening radiotherapy failures and tumor recurrences, and the mechanism of which is not yet clear.Cancer cells maintain a high level of aerobic glycolysis (the Warburg effect) and are among the immune microenvironment, exploring the influences of radiotherapy on tumor cell metabolism and tumor immune microenvironment help to further reveal the molecular and immune mechanisms that lead to tumor recurrence after radiotherapy.Our previous study found that radiotherapy could promote tumor cell glycolysis and producing more lactic acid and could increse the number and functinal genes expression of MDSC in tumor microenvironment.Recent reports and our experiments all have found that lactic acid could promote myeloid origin suppressor cells (MDSC) generation and function.Therefore,we assume that radiotherapy could regulate tumor cell metabolism and promote lactic acid secretion, then the secreted lactic acid could affect the tumor immune microenvironment and promote the generation and function of MDSC,and lactic acid-induced MDSC may cause tumor recurrence by the mechanism of promoting immune suppression and tumor re-proliferation. The project plans to use the tumor animal model and clinical samples to explore whether radiotherapy could regulate tumor cells metabolism and could affect the MDSC in the immune microenvironment by the upregulated metabolite lactate acid.Then we attempt to reveal the molecular pathways of radiation affecting tumor metabolism, the molecular mechanisms of lactic acid regulating MDSC generation and function. Through this research we hope to provide a theoretical basis for developing a new therapeutic target that could enhance the therapeutic effect of radiotherapy.

放射治疗是肿瘤治疗的重要手段，但是放疗后的肿瘤复发导致放疗失败，其机制尚未清楚。肿瘤细胞具有特异的代谢机制并且处于多种免疫细胞构成的免疫微环境中，深入研究放疗-肿瘤代谢-肿瘤免疫微环境之间的关系有助于揭示放疗后肿瘤复发的分子和免疫机制。申请人在前期工作中发现放疗促进肿瘤细胞产生更多乳酸，放疗后肿瘤患者和小鼠肿瘤模型中髓样来源抑制性细胞（MDSC）的数量和功能显著上调。因此，我们假设放疗可能通过促进代谢产物乳酸分泌而调控微环境中免疫抑制性的MDSC进而影响肿瘤复发，体外实验结果也初步证实了放疗后增加的乳酸可以促进MDSC的上调，但是放疗调控乳酸和乳酸调控MDSC的分子机制尚未清楚，因此本课题拟通过体外实验、小鼠模型以及临床样本分析，进一步验证放疗是否通过乳酸调控MDSC而导致肿瘤复发，探究放疗促进乳酸分泌以及乳酸调控MDSC的详细分子机制，为放射治疗开发新的治疗靶点、增强治疗效果提供依据。

放射治疗是肿瘤治疗的重要手段，但是放疗抵抗常常导致放疗失败和肿瘤进展。肿瘤细胞处于多种免疫细胞构成的免疫微环境中，除了放疗后肿瘤细胞自身变化导致的放疗抵抗以外，抑制性免疫微环境是肿瘤产生放疗抵抗的重要原因，但是放疗与肿瘤免疫微环境之间的相互作用及机制尚未阐明。本项目首先探究了放疗对于肿瘤组织抑制性免疫微环境的影响，我们检测了放疗后的肿瘤病人、自发肿瘤和原位移植瘤小鼠肿瘤组织中MDSCs的功能状态，发现放疗可以显著促进肿瘤组织中MDSCs的活化，增强其免疫抑制功能。肿瘤代谢产物可以调控肿瘤免疫微环境，我们发现放疗可以促进肿瘤细胞Warburg效应增强及其产物乳酸分泌的增加。我们进一步探究了放疗增加的乳酸分泌是否调控免疫微环境中MDSCs的功能，体外给予乳酸刺激可以促进MDSCs功能基因表达上调，在体外和体内干扰乳酸生成均可以显著抑制放疗导致的MDSCs的活化，这些结果证实了乳酸参与了放疗对MDSCs免疫抑制功能的调控作用。在此基础上，我们进一步探究了乳酸调控MDSCs活化的详细分子机制，结果发现HIF-1α分子和mTOR信号通路对于乳酸介导的MDSCs活化至关重要，乳酸分子通过GPR81/mTOR/HIF-1α/STAT3信号通路调控MDSCs的活化。我们进一步在多种小鼠肿瘤模型和病人临床标本中证实了放疗后肿瘤细胞增强分泌的乳酸分子及其上调的HIF-1α信号在活化MDSCs、诱导抑制性免疫微环境形成以及放疗抵抗产生中的重要作用。本项目研究阐明了放疗后肿瘤细胞代谢产物的变化对肿瘤抑制性免疫微环境的调控作用，从抑制性免疫微环境角度揭示了肿瘤放疗抵抗产生的可能机制。本项目的完成为肿瘤放射治疗提供了新的潜在靶点，为克服放疗抵抗、增强放射治疗效果提供了新的治疗思路和策略，放射治疗联合靶向代谢和免疫的治疗手段可能会产生更好的肿瘤治疗效果。