Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada.
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Skelet Muscle. 2019 Sep 14;9(1):24. doi: 10.1186/s13395-019-0209-y.
Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients.
Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; μm) and radiologically (lumbar skeletal muscle index, SMI; cm/m by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort.
T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3-CD4+ cells were identified. Muscle fiber CSA (μm) was positively correlated (Spearman's r = > 0.45; p = < 0.05) with the total number of T cells, CD4, and CD8 T cells and granulocytes/phagocytes. In addition, patients with the smallest SMI exhibited fewer CD8 T cells within their muscle. Consistent with this, further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively associated (Pearson's r = ≥ 0.5; p = <0.0001) with key genes within muscle catabolic pathways for signaling (ACVR2B), ubiquitin proteasome (FOXO4, TRIM63, FBXO32, MUL1, UBC, UBB, UBE2L3), and apoptosis/autophagy (CASP8, BECN1, ATG13, SIVA1).
The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3-CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.
炎症是肌肉消耗的公认诱因。在损伤和肌病研究中，骨骼肌肉与免疫细胞之间的相互作用赋予了促炎环境，通过多种机制影响肌肉丢失；然而，这在癌症环境中尚未得到探索。本研究通过鉴定癌症患者肌肉中免疫细胞群体的表型及其与肌肉质量的关系，来研究肌肉的局部免疫环境。
从癌症患者（n=30，91%为胃肠道恶性肿瘤）中采集术中肌肉活检。通过组织学（肌纤维横截面积，CSA；μm）和影像学（腰椎骨骼肌指数，SMI；CT 计算的 cm/m）评估肌肉质量。通过免疫组织化学评估 T 细胞（CD4 和 CD8）和粒细胞/吞噬细胞（CD11b、CD14 和 CD15）。对第二例癌症患者队列的肌肉进行微阵列分析。
鉴定出 T 细胞（CD3+）、粒细胞/吞噬细胞（CD11b+）和 CD3-CD4+细胞。肌纤维 CSA（μm）与 T 细胞总数、CD4 和 CD8 T 细胞以及粒细胞/吞噬细胞呈正相关（Spearman's r > 0.45；p < 0.05）。此外，SMI 最小的患者其肌肉中 CD8 T 细胞较少。与此一致，进一步的基因相关性分析表明，CD8 T 细胞的存在与肌肉分解代谢途径中的关键基因呈负相关（Pearson's r ≥ 0.5；p < 0.0001），这些基因包括信号转导（ACVR2B）、泛素蛋白酶体（FOXO4、TRIM63、FBXO32、MUL1、UBC、UBB、UBE2L3）和凋亡/自噬（CASP8、BECN1、ATG13、SIVA1）。
癌症患者的骨骼肌免疫环境由适应性和固有免疫的免疫细胞群组成。T 细胞、粒细胞/吞噬细胞和 CD3-CD4+细胞与肌肉质量测量的相关性表明，在癌症患者中，免疫细胞数量与肌肉质量状态之间呈正相关。进一步的基因相关性分析表明，CD8 T 细胞的存在与肌肉分解代谢的成分呈负相关。
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