T-cell infiltration profile in musculoskeletal tumors
T-cell infiltration profile in musculoskeletal tumors
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DOI：
10.1002/jor.24890
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发表时间：
2020-10-30
影响因子：
2.8
通讯作者：
Raz, Abraham
中科院分区：
文献类型：
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作者：
Nakajima, Kosei;Raz, Abraham
肌肉骨骼肿瘤的免疫治疗在临床上仍然具有挑战性，需要开发基因工程/过继外源性免疫细胞或鉴定可用于治疗以改善患者结局的新分子靶标。最近，内源性B细胞浸润到肿瘤微环境似乎是一个重要的有前途的预后因素控制肿瘤进展的肌肉骨骼恶性肿瘤。在此，我们通过分析1366例患者和23种组织学类型的CD 3E、CD 4和CD 8A的表达谱来探讨T细胞浸润水平。数据显示，与正常骨相比，骨肿瘤中CD 3E和CD 8A的表达主要受到抑制。CD 4在软骨肉瘤和骨巨细胞瘤等肿瘤中表达上调，而在其他肿瘤中表达相对较低。同样，对于软组织肉瘤，T细胞相关分子的表达在很大程度上受到抑制。仅在横纹肌肉瘤患者中，CD 3E和CD 8A表达显著上调，显示免疫活性肿瘤的性质。为了可视化横纹肌肉瘤的免疫微环境，我们开发了一种新的软件，旨在分析众多的细胞与细胞和配体与受体的相互作用，即Environmentome。这导致了CD 8（+）T细胞和横纹肌肉瘤之间通过半乳糖凝集素3-LAG 3结合的分子相互作用的鉴定，半乳糖凝集素3-LAG 3结合是最近鉴定的新的免疫检查点。总之，肌肉骨骼肿瘤可被定义为免疫静止型肿瘤，因此靶向半乳糖凝集素-3和/或免疫浸润剂在这些免疫非炎症性肌肉骨骼肿瘤中可能至关重要，可加速免疫应答。
Immunotherapy of musculoskeletal tumors remains clinically challenging and requires the development of gene-engineered/adoptive exogenous immune cells or the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Recently, endogenous B-cell infiltration into tumor microenvironments appears to be an essential promising prognostic factor controlling tumor progression in musculoskeletal malignancy. Here, we explored the level of T-cell infiltration by analyzing expression profiles of CD3E, CD4, and CD8A in 1366 patients and 23 histological types. The data revealed that CD3E and CD8A expressions were predominantly inhibited in bone tumors when compared with normal bone. CD4 expression was upregulated in limited types of tumors, including chondrosarcoma and giant cell tumor of bone, whereas other tumors demonstrated relatively lower expressions. Similarly, regarding soft tissue sarcoma, the expression of T-cell-related molecules was largely inhibited. Only in patients with rhabdomyosarcoma, CD3E and CD8A expressions were significantly upregulated, showing the nature of immune-active tumor. To visualize the immunological microenvironment of rhabdomyosarcoma, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome. It has led to the identification of molecular interactions between CD8(+) T cell and rhabdomyosarcoma via Galectin3-LAG3 binding, which is a novel immune checkpoint recently identified. In conclusion, musculoskeletal tumors may be defined as immune-quiescent tumors, whereby targeting Galectin-3 and/or immune-infiltrative agents could be crucial in these immunologically noninflamed musculoskeletal tumors, accelerating immunotherapeutic response.