Coleman Michael F, Liu Kristyn A, Pfeil Alexander J, Etigunta Suhas K, Tang Xiaohu, Fabela Salvador, Lashinger Laura M, Cui Zhengrong, Hursting Stephen D
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Nutritional Sciences, University of Texas, Austin, TX 77843, USA.
Cancers (Basel). 2021 Dec 18;13(24):6359. doi: 10.3390/cancers13246359.
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, and effective therapies for PDAC are currently lacking. Moreover, PDAC is promoted and exacerbated by obesity, while cachexia and sarcopenia are exceptionally common comorbidities that predict both poor survival and treatment response. Managing PDAC with immunotherapies has thus far proven ineffective, partly due to the metabolically hostile tumor microenvironment. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine commonly used as a dietary supplement to boost muscle growth and immune function, may be an attractive candidate to augment PDAC therapy. We therefore sought to test the hypothesis that HMB would enhance antitumor immunity while protecting mouse muscle mass. Control and diet-induced obese C57BL/6 male mice bearing subcutaneously injected Panc02 tumors were supplemented with 1% HMB and treated with or without 50 mg/kg gemcitabine ( = 15/group). HMB was associated with reduced muscle inflammation and increased muscle fiber size. HMB also reduced tumor growth and promoted antitumor immunity in obese, but not lean, mice, independent of the gemcitabine treatment. Separately, in lean tumor-bearing mice, HMB supplementation promoted an anti-PD1 immunotherapy response ( = 15/group). Digital cytometry implicated the decreased abundance of M2-like macrophages in PDAC tumors, an effect that was enhanced by anti-PD1 immunotherapy. We confirmed that HMB augments M1-like macrophage (antitumor) polarization. These preclinical findings suggest that HMB has muscle-sparing and antitumor activities against PDAC in the context of obesity, and that it may sensitize otherwise nonresponsive PDAC to immunotherapy.
胰腺导管腺癌（PDAC）是美国癌症相关死亡的第四大主要原因，目前缺乏针对PDAC的有效治疗方法。此外，肥胖会促进并加剧PDAC，而恶病质和肌肉减少症是极为常见的合并症，预示着患者生存率低且治疗反应不佳。迄今为止，用免疫疗法治疗PDAC已被证明无效，部分原因是肿瘤微环境具有代谢敌意。β-羟基-β-甲基丁酸酯（HMB）是亮氨酸的一种代谢产物，常用作膳食补充剂以促进肌肉生长和增强免疫功能，它可能是增强PDAC治疗效果的一个有吸引力的候选物质。因此，我们试图验证HMB能增强抗肿瘤免疫力并保护小鼠肌肉质量这一假设。给皮下注射了Panc02肿瘤的对照小鼠和饮食诱导肥胖的C57BL/6雄性小鼠补充1%的HMB，并给予或不给予50mg/kg吉西他滨治疗（每组n = 15）。HMB与肌肉炎症减轻和肌纤维尺寸增加有关。HMB还能减少肥胖小鼠（而非瘦小鼠）的肿瘤生长并促进抗肿瘤免疫，这与吉西他滨治疗无关。另外，在瘦的荷瘤小鼠中，补充HMB可促进抗PD1免疫治疗反应（每组n = 15）。数字细胞计数法显示，PDAC肿瘤中M2样巨噬细胞的丰度降低，抗PD1免疫治疗可增强这一效果。我们证实，HMB可增强M1样巨噬细胞（抗肿瘤）极化。这些临床前研究结果表明，HMB在肥胖情况下对PDAC具有保护肌肉和抗肿瘤活性，并且它可能使原本无反应的PDAC对免疫治疗敏感。
