Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML
Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML
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DOI：
10.1038/s41375-018-0175-0
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发表时间：
2018-07-01
期刊：
影响因子：
11.4
通讯作者：
Mustjoki, Satu
中科院分区：
文献类型：
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作者：
Bruck, Oscar;Blom, Sami;Mustjoki, Satu
越来越多的证据表明，免疫系统影响慢性粒细胞白血病(CML)的预后，但白血病骨髓(BM)微环境的详细免疫学成分尚不清楚。我们的目的是描述CML BM的免疫状况，并预测目前酪氨酸激酶抑制剂(TKI)治疗的分子缓解4.0(MR4.0)的治疗目标。应用多重免疫组织化学(MIHC)和自动图像分析技术，对56例CML患者和14例正常对照的骨髓组织进行了30种肿瘤免疫表型标志物的研究。与对照组相比，CML患者的CD4+和CD8+T细胞表达了更高水平的可能的耗竭标志物PD1、TIM3和CTLA4。与配对的外周血(PB)样本相比，骨髓中PD1的表达更高，在TKI治疗期间，PD1的表达降低。结合临床参数和免疫指标，低的CD4+T细胞比例、高比例的PD1+TIM3-CD8+T细胞和高的外周血中性粒细胞计数最能预测低MR4.0的可能性。在用流式细胞术分析的验证队列(n=52)中，低的CD4+T细胞比例和高的外周血中性粒细胞计数也可以预测MR4.0。综上所述，CML BM的特点是免疫抑制和免疫生物标志物预测MR4.0，因此有必要在CML治疗中进一步测试免疫调节药物。
Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+ TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.