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骨肉瘤中的腫瘤浸潤(rùn)淋巴細(xì)胞和癌癥標(biāo)志物：對(duì)患者生存的影響

發(fā)表日期：2022-01-19

Tumor-Infiltrating Lymphocytes and Cancer Markers in Osteosarcoma: Influence on Patient Survival

骨肉瘤中的腫瘤浸潤(rùn)淋巴細(xì)胞和癌癥標(biāo)志物：對(duì)患者生存的影響

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) 是最常見的高級(jí)別原發(fā)性骨腫瘤，主要影響年輕人。盡管已經(jīng)做出努力來(lái)解決免疫相關(guān)因素在 OST 中的重要性，但仍有很多需要了解。本研究的目的是評(píng)估腫瘤浸潤(rùn)淋巴細(xì)胞 (TIL)、參與腫瘤生物學(xué)的蛋白質(zhì)的表達(dá)及其對(duì) OST 患者臨床結(jié)果的影響。我們的研究結(jié)果表明，腫瘤浸潤(rùn)性 CD4+ 細(xì)胞的存在為患者提供了保護(hù)，并且 CD8+ 細(xì)胞對(duì)患者的總生存期 (OS) 和無(wú)進(jìn)展生存期 (PFS) 有顯著影響。此外，觀察到腫瘤浸潤(rùn)性 CD4+ 細(xì)胞與腫瘤樣品中 CD44s 表達(dá)的存在密切相關(guān)。

三角細(xì)胞搖瓶

Conventional osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults [1]. The neoplasm arises preferentially in the metaphyses of the long bones with the highest incidence around the knee [2]. 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 [3]. 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 [6]. Despite targeted or immune therapies being widely used in various cancers, so far no other strategies have been introduced in OST clinical practice [3]. 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 [10]. 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].

血清培養(yǎng)基瓶

傳統(tǒng)骨肉瘤（osteosarcoma，OST）是最常見的高級(jí)別原發(fā)性骨腫瘤，主要好發(fā)于青壯年[ 1 ]。腫瘤優(yōu)先出現(xiàn)在長(zhǎng)骨干骺端，膝關(guān)節(jié)周圍發(fā)病率最高 [ 2 ]。一般來(lái)說(shuō)，治療策略包括局部控制手術(shù)，結(jié)合術(shù)前和術(shù)后全身化療，以減少疾病傳播的可能性 [ 3 ]。對(duì)于本地化的 OST，5 年生存率為 70%；然而，OST 經(jīng)常發(fā)生轉(zhuǎn)移，復(fù)發(fā)或轉(zhuǎn)移性疾病的 5 年生存率急劇下降至 20% 以下 [ 4 , 5]。在晚期 OST 中，對(duì)化療的多藥耐藥也是一個(gè)反復(fù)出現(xiàn)的問(wèn)題，唯一的根治性治療是完全手術(shù)切除轉(zhuǎn)移灶，這在大多數(shù)情況下都是一個(gè)具有挑戰(zhàn)性的過(guò)程 [ 6 ]。盡管靶向或免疫療法被廣泛用于各種癌癥，但迄今為止，在 OST 臨床實(shí)踐中尚未引入其他策略 [ 3 ]。因此，臨床結(jié)果和目前治療 OST 患者的選擇并不令人滿意，需要新的有效治療策略。

根據(jù)全基因組泛癌分析 (PCAWG) 等 [ 7 , 8 , 9 ]，OST 表現(xiàn)出高度可信的染色體碎裂和大量基因組結(jié)構(gòu)改變，但腫瘤突變負(fù)擔(dān)低。因此，在這種情況下，靶向治療的使用受到限制。另一方面，探索新型 OST 免疫療法或免疫相關(guān)生物標(biāo)志物以預(yù)測(cè)治療反應(yīng)的興趣一直在增加 [ 10 ]。此外，骨肉瘤細(xì)胞產(chǎn)生的類骨質(zhì)基質(zhì)被免疫細(xì)胞包圍，包括血管、間充質(zhì)細(xì)胞和基質(zhì)細(xì)胞。因此，很明顯，免疫細(xì)胞是腫瘤維持和進(jìn)展的積極參與者 [ 11 , 12, 13 ]，并且腫瘤細(xì)胞和免疫細(xì)胞之間的串?dāng)_，通過(guò)可溶性因子的釋放和細(xì)胞與細(xì)胞的接觸，對(duì)于 OST 微環(huán)境至關(guān)重要 [ 1 , 14 , 15 , 16 ]。

5L高效搖瓶

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.

本研究的主要發(fā)現(xiàn)是浸潤(rùn) CD4 T 細(xì)胞的保護(hù)特性、CD8 T 細(xì)胞對(duì)存活的影響以及浸潤(rùn)的 CD4 T 細(xì)胞與 CD44s 表達(dá)之間的強(qiáng)關(guān)聯(lián)。這項(xiàng)研究證實(shí)了在 OST 的背景下研究能夠被招募并發(fā)揮其對(duì)抗腫瘤細(xì)胞功能的細(xì)胞的重要性。腫瘤標(biāo)志物的表達(dá)也是一個(gè)需要考慮的問(wèn)題，應(yīng)該進(jìn)一步探索，以對(duì)促進(jìn)腫瘤生長(zhǎng)和逃逸的機(jī)制產(chǎn)生新的認(rèn)識(shí)。因此，可能會(huì)發(fā)現(xiàn)具有預(yù)測(cè)價(jià)值的新靶點(diǎn)或生物標(biāo)志物，可能有助于對(duì)患者進(jìn)行分層并監(jiān)測(cè)對(duì)治療的反應(yīng)。