免疫反应基因和肿瘤微环境组成中的单核苷酸变异可预测套细胞淋巴瘤的进展。
Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma.
机构信息
Department of Pathology, Faculty of Medical Sciences, University of Campinas, Distrito de Barão Geraldo, Campinas, SP, Brazil.
Department of Internal Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
出版信息
BMC Cancer. 2021 Mar 1;21(1):209. doi: 10.1186/s12885-021-07891-9.
BACKGROUND
There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL.
METHODS
We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models.
RESULTS
High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFβ levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival.
CONCLUSIONS
Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.
背景
有证据表明肿瘤微环境（TME）组成与抗肿瘤免疫反应有关，并可能预测各种非霍奇金淋巴瘤亚型的结局。然而，在套细胞淋巴瘤（MCL）这种罕见且侵袭性疾病的情况下，对于 TME 成分缺乏详细的研究，以及患者样本中它们之间的综合分析。此外，从遗传角度来看，已知免疫反应基因中的单核苷酸变异（SNV）是免疫的重要调节剂之一。目前，尚不确定候选免疫反应基因中的 SNV 和 TME 组成是否能够改变 MCL 的预后。
方法
我们使用免疫组织化学方法在 88 例 MCL 活检标本中评估了详细的 TME 组成，使用像素计数（Aperio 系统）自动分析。我们还对 95 例 MCL 患者中候选免疫反应基因（IL12A、IL2、IL10、TGFB1、TGFBR1、TGFBR2、IL17A、IL17F）中的 SNV 进行了基因分型。我们测试了 SNV 是否可以调节肿瘤部位的相应蛋白表达和 TME 组成。最后，我们提出了在利妥昔单抗治疗患者中考虑免疫组化和 SNV 模型的生存模型。
结果
高 FOXP3/CD3 比值（p=0.001）、高 IL17A 水平（p=0.003）和低 IL2 水平（p=0.03）是生存较差的独立免疫组化预测因素。由大量巨噬细胞和高 Ki-67 指数组成的主要成分也会使结局恶化（p=0.02）。在 SNV 模型中，IL10 的 CC 单倍型（p<0.01）、IL2 rs2069762 的 GG 基因型（p=0.02）和 TGFBR2 rs3087465 的 AA+AG 基因型（p<0.01）是独立的预后预测因素。最后，TGFB1 rs6957 的 GG 基因型与肿瘤 TGFβ 水平较低（p=0.03）和 CD163+巨噬细胞较少（p=0.01）相关，但不影响患者的生存。
结论
我们的结果表明，TME 组成在 MCL 中具有相关的生物学作用。在这种情况下，T 调节细胞、IL17A 和 IL2 的免疫组织化学检测，以及 IL10、TGFBR2 和 IL2 中的 SNV 基因分型，可能是该疾病的新的预后因素，需要进一步验证。
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