Tumor-Infiltrating Lymphocytes and Cancer Markers in Osteosarcoma: Influence on Patient Survival
Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to patients, and that CD8+ cells have a significant impact on the patient’s overall survival (OS) and progression-free survival (PFS). In addition, a strong association of tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. These findings reinforce the idea that TIL and the expression of tumor markers should be taken into consideration in order to improve OST treatment and management.
骨肉瘤 (OST) 是最常见的高级别原发性骨肿瘤，主要影响年轻人。尽管已经做出努力来解决免疫相关因素在 OST 中的重要性，但仍有很多需要了解。本研究的目的是评估肿瘤浸润淋巴细胞 (TIL)、参与肿瘤生物学的蛋白质的表达及其对 OST 患者临床结果的影响。我们的研究结果表明，肿瘤浸润性 CD4+ 细胞的存在为患者提供了保护，并且 CD8+ 细胞对患者的总生存期 (OS) 和无进展生存期 (PFS) 有显着影响。此外，观察到肿瘤浸润性 CD4+ 细胞与肿瘤样品中 CD44s 表达的存在密切相关。
Conventional osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults . The neoplasm arises preferentially in the metaphyses of the long bones with the highest incidence around the knee . In general, the therapeutic strategy consists of local control surgery, combined with pre- and postoperatively systemic chemotherapy to reduce the likelihood of the disease spreading . For localized OST, the 5-year rate of survival is 70%; however, OST often metastasizes and the 5-year survival rate for recurrent or metastatic disease drastically declines to less than 20% [4,5]. In advanced OST, multidrug resistance to chemotherapy is also a recurrent problem, and the only curative treatment is complete surgical resection of the metastasis, which is a challenging process most of the time . Despite targeted or immune therapies being widely used in various cancers, so far no other strategies have been introduced in OST clinical practice . As such, the clinical outcomes, and the current options to treat OST patients, are unsatisfactory and novel effective treatment strategies are needed.
OST exhibits high-confidence chromothripsis and a high number of genomic structural alterations, but low tumor mutational burden according to the Pan-Cancer Analysis of Whole Genomes (PCAWG) and others [7,8,9]. Therefore, the use of targeted therapy is limited in this context. On the other hand, the interest in the exploration of novel OST-immunotherapies or immune-related biomarkers to predict the response to therapy has been increasing . Moreover, the osteoid matrix produced by osteosarcoma cells is surrounded by immune cells, amongst blood vessels, mesenchymal and stromal cells. As such, it is evident that immune cells are active players in tumor sustainment and progression [11,12,13], and that the crosstalk between tumor cells and immune cells, through the release of soluble factors and cell–cell contact, is essential for the OST microenvironment [1,14,15,16].
传统骨肉瘤（osteosarcoma，OST）是最常见的高级别原发性骨肿瘤，主要好发于青壮年[ 1 ]。肿瘤优先出现在长骨干骺端，膝关节周围发病率最高 [ 2 ]。一般来说，治疗策略包括局部控制手术，结合术前和术后全身化疗，以减少疾病传播的可能性 [ 3 ]。对于本地化的 OST，5 年生存率为 70%；然而，OST 经常发生转移，复发或转移性疾病的 5 年生存率急剧下降至 20% 以下 [ 4 , 5]。在晚期 OST 中，对化疗的多药耐药也是一个反复出现的问题，唯一的根治性治疗是完全手术切除转移灶，这在大多数情况下都是一个具有挑战性的过程 [ 6 ]。尽管靶向或免疫疗法被广泛用于各种癌症，但迄今为止，在 OST 临床实践中尚未引入其他策略 [ 3 ]。因此，临床结果和目前治疗 OST 患者的选择并不令人满意，需要新的有效治疗策略。
根据全基因组泛癌分析 (PCAWG) 等 [ 7 , 8 , 9 ]，OST 表现出高度可信的染色体碎裂和大量基因组结构改变，但肿瘤突变负担低。因此，在这种情况下，靶向治疗的使用受到限制。另一方面，探索新型 OST 免疫疗法或免疫相关生物标志物以预测治疗反应的兴趣一直在增加 [ 10 ]。此外，骨肉瘤细胞产生的类骨质基质被免疫细胞包围，包括血管、间充质细胞和基质细胞。因此，很明显，免疫细胞是肿瘤维持和进展的积极参与者 [ 11 , 12, 13 ]，并且肿瘤细胞和免疫细胞之间的串扰，通过可溶性因子的释放和细胞与细胞的接触，对于 OST 微环境至关重要 [ 1 , 14 , 15 , 16 ]。
The major findings of this study were the protective character of infiltrating CD4 T cells, the influence of CD8 T cells on survival and the strong association between the infiltrated CD4 T cells and the CD44s expression. This study confirmed the importance of studying the cells that are able to be recruited and exert their function against tumor cells in the context of OST. The expression of tumor markers is also a matter to be considered and should be further explored to bring new insights about the mechanisms that promote the tumor’s growth and escape. Thus, the identification of novel targets or biomarkers with a predictive value that may be useful to stratify patients and monitor the response to therapy could occur, as well as assisting with the development of immunotherapy strategies to improve the effects of cytotoxic TIL on the eradication of tumor cells.
本研究的主要发现是浸润 CD4 T 细胞的保护特性、CD8 T 细胞对存活的影响以及浸润的 CD4 T 细胞与 CD44s 表达之间的强关联。这项研究证实了在 OST 的背景下研究能够被招募并发挥其对抗肿瘤细胞功能的细胞的重要性。肿瘤标志物的表达也是一个需要考虑的问题，应该进一步探索，以对促进肿瘤生长和逃逸的机制产生新的认识。因此，可能会发现具有预测价值的新靶点或生物标志物，可能有助于对患者进行分层并监测对治疗的反应。
关键词： osteosarcoma,tumor-infiltrating lymphocytes,tumor markers,tumor microenvironment,survival,骨肉瘤,肿瘤浸润淋巴细胞,肿瘤标志物,肿瘤微环境,生存