木糖可促进三阴性乳腺癌免疫疗效

学术   2024-11-10 08:33   泰国  

  三阴性乳腺癌是雌激素受体、孕激素受体、HER2均为阴性的一类乳腺癌,大约占全部乳腺癌的15%,与其他乳腺癌相比,其异质性、侵袭性、复发转移率相对较高,一直以来是临床治疗的难题。此外,虽然化疗联合免疫治疗已经对三阴性乳腺癌的治疗取得极大成功,但是许多患者仍对免疫治疗并不敏感。2019年,复旦大学附属肿瘤医院揭示了三阴性乳腺癌内部的免疫微环境异质性,提出三阴性乳腺癌“复旦免疫微环境分型”,即免疫沙漠型、免疫失活型、免疫炎症型。同时,复旦大学附属肿瘤医院前期研究亦系统性解析了三阴性乳腺癌代谢图谱,揭示了其代谢的异质性。深入研究三阴性乳腺癌免疫代谢失调的分子机制,探索潜在促进三阴性乳腺癌“冷肿瘤”转变为“热肿瘤”的代谢靶点,是亟待解决的临床科学问题。

  2024年11月8日,美国细胞出版社旗舰期刊《医学》在线发表复旦大学附属肿瘤医院吴怀亮①、龚悦①✉、凌云霄、邬思雨、吉芃、赵谦、何李华、邵志敏、江一舟✉、柳光宇✉等学者的研究报告,首次发现关键代谢酶二氢二醇脱氢酶(DHDH)与三阴性乳腺癌“冷肿瘤”微环境形成密切相关,并发现DHDH可以通过介导右旋木糖代谢促进三阴性乳腺癌免疫逃逸,提出外源补充右旋木糖联合免疫检查点抑制剂可以作为DHDH高表达三阴性乳腺癌潜在的治疗策略。

  众所周知,地球生物体内天然氨基酸均为左旋、天然糖类均为右旋木糖亦不例外。因此,以下将将右旋木糖简称为木糖

  该单中心回顾研究利用前期建立的三阴性乳腺癌多组学队列,对465例三阴性乳腺癌患者的代谢基因进行分析,筛选出显著高表达于三阴性乳腺癌免疫沙漠型及显著低表达于免疫炎症型的DHDH。DHDH主要介导的代谢反应包括烟酰胺腺嘌呤二核苷酸磷酸(NADP)依赖性芳香烃氧化为相应的邻苯二酚木糖转化为木糖-1,5-内酯。体内外实验发现DHDH促进三阴性乳腺癌的生长并依赖免疫微环境CD8阳性T细胞,并且一系列生物信息学分析鉴定到DHDH的下游蛋白PSMB9。免疫蛋白酶体PSMB9可影响抗原降解及下游免疫反应的激活,该研究发现过表达DHDH可显著抑制PSMB9的表达及免疫浸润。

  进一步机制研究提示,DHDH介导免疫逃逸依赖于其代谢酶活性。非靶向代谢物检测和木糖检测提示,木糖缺乏可能是DHDH高表达冷肿瘤表型的原因。该研究进一步揭示外源补充木糖可显著促进下游PSMB9的表达,并进一步提高三阴性乳腺癌免疫浸润及增敏DHDH高表达三阴性乳腺癌免疫检查点抑制剂疗效。此外,三阴性乳腺癌患者的临床标本分析提示尿液木糖水平与肿瘤CD8表达呈显著正相关。


  因此,该研究结果表明,补充木糖或者富含木糖的膳食模式联合免疫治疗有望为DHDH高表达的三阴性乳腺癌“冷肿瘤”提供新的临床治疗策略,故有必要进一步开展前瞻临床研究进行验证。

  木糖为白色细针状结晶或结晶性粉末,可溶于水和温热乙醇,不溶于乙醚,有还原性、右旋光性和变旋现象,略有特殊气味和爽口甜味,甜味相当于蔗糖的0.4倍。木糖广泛存在于各种植物中,可从白桦、覆盆子、玉米、燕麦壳等植物原料中提取,目前主要产自中国。木糖以多糖的形式天然存在于植物,可以从黑木耳或农产品废弃物(如棉桃的外皮,玉米的秸秆、穗轴)提取,通常以草木类、种子壳、木材等多缩木糖含量高的植物作为原料,与硫酸或盐酸进行加水分解,使木材中属半纤维素的木聚糖水解成木糖,然后用酵母发酵以除去葡萄糖,再精制浓缩而成。人体无法消化和利用木糖,木糖不能被消化酶分解,而是直接经空肠黏膜吸收,不在体内代谢,直接从肾排出,因此被用作无热量的甜味剂,以满足糖尿病患者和爱吃甜食却又担心发胖者的需求。医学上的木糖吸收试验就是通过测定患者在空腹口服木糖5小时后尿内的木糖排出量而反映出患者的小肠吸收功能。将木糖催化氢化还原后就得到木糖醇,木糖醇用作甜味剂,用途更加广泛,不过目前尚不明确木糖醇能否促进三阴性乳腺癌免疫疗效。


Med. 2024 Nov 8. IF: 12.8


DHDH-mediated D-xylose metabolism induces immune evasion in triple-negative breast cancer.


Huai-liang Wu, Yue Gong, Yun-xiao Ling, Si-yu Wu, Peng Ji, Qian Zhao, Li-Hua He, Zhi-Ming Shao, Yi-Zhou Jiang, Guang-yu Liu.


Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Sun Yat-sen University Cancer Center, Guangzhou, China.


CONTEXT AND SIGNIFICANCE: Triple-negative breast cancer (TNBC) exhibits resistance to immunotherapy due to its heterogeneous metabolic characteristics. Deciphering the metabolic mechanisms regulating anticancer immunity will provide new insights into therapeutic strategies for TNBC. Wu et al. performed bioinformatics analysis using FUSCC TNBC multi-omics data and identified a key metabolic enzyme, dihydrodiol dehydrogenase (DHDH), which is correlated with low immune infiltration. They found that D-xylose supplementation in vivo promoted CD8+ T cell infiltration and the expression of cytotoxic markers and increased the sensitivity of DHDH-overexpressing tumors to immunotherapy. Therefore, these findings may provide theoretical support for incorporating D-xylose or a xylose-rich diet alongside immunotherapy in TNBC patients with high DHDH expression.


HIGHLIGHTS

  • DHDH is an upregulated enzyme in “cold tumors” of TNBC

  • DHDH promotes tumor growth via immune regulation mediated by its enzymatic activity

  • D-xylose promotes immune infiltration via upregulation of PSMB9

  • D-xylose supplementation potentiates the efficacy of immunotherapy in TNBC


BACKGROUND: Although the prognosis of triple-negative breast cancer (TNBC) has significantly improved in the era of immunotherapy, many TNBC patients are resistant to therapies, and their disease progresses rapidly. Deciphering the metabolic mechanisms regulating anticancer immunity will provide new insights into therapeutic strategies for TNBC.


METHODS: In this study, we performed bioinformatics analysis in our multi-omics TNBC database and identified that a metabolic enzyme, dihydrodiol dehydrogenase (DHDH), might promote the phenotype of “cold tumor” in TNBC. The biological function of DHDH was verified by in vitro and in vivo functional experiments, and the potential molecular mechanism of DHDH promoting TNBC immune escape was further explored.


FINDINGS: Mechanistically, DHDH mediated the synthesis and depletion of the substrate D-xylose and inhibited the activation of the proteasome subunit beta type 9 (PSMB9) and further induction of the immune response. We demonstrated that D-xylose supplementation could enhance the proliferation of CD8+ T cells and the expression of cytotoxic markers against cocultured DHDH-wild type (WT) cells. Consistently, D-xylose supplementation in vivo promoted CD8+ T cell infiltration and the expression of cytotoxic markers and increased the sensitivity of DHDH-overexpressing tumors to immune checkpoint blockade (ICB).


CONCLUSIONS: Our findings reveal that a D-xylose-regulated PSMB9-dependent pathway governs tumor-intrinsic immunogenicity and, hence, the sensitivity to ICB, which may provide approaches to promote the “cold-to-hot” transition in TNBC.


FUNDING: This study was funded by the National Key Research and Development Plan of China, Shanghai Science and Technology Commission, National Natural Science Foundation of China, and China Postdoctoral Science Foundation.


KEYWORDS: triple-negative breast cancer, dihydrodiol dehydrogenase, d-xylose, proteasome subunit beta type 9, immunotherapy


DOI: 10.1016/j.medj.2024.10.012































SIBCS
上海国际乳腺癌论坛(Shanghai International Breast Cancer Symposium)
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