Abstract：
OBJECTIVE: Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune cells.
METHODS: Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape.
RESULTS: Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples.
CONCLUSIONS: Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG.
METHODS: Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape.
RESULTS: Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples.
CONCLUSIONS: Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG.
摘要：
目的：揭示多巴胺激动剂治疗在人泌乳素腺瘤肿瘤和邻近的间质和免疫细胞中的靶点和脱靶作用的潜在机制。
方法：通过单细胞RNA测序（scRNA-seq）分析了来自3名卡麦角林（CBG）治疗和2名初治患者的5例手术切除的泌乳素瘤，以比较细胞组成和转录景观。
结果：包括肿瘤在内的六种主要细胞群（88.2％），免疫(5.6%)，基质（4.9%），祖细胞（0.6%），增殖细胞（0.4%），观察到红细胞（0.2％）。来自CBG治疗患者的肿瘤细胞表达较低水平的调节激素分泌的基因，如SCG2，VGF，TIMP1,NNAT,和CALD1，与CBG对激素加工和分泌的抑制作用一致。有趣的是,我们还观察到CBG处理的组织中CD8+T细胞数量增加.这些细胞毒性CD8+T细胞表达杀伤颗粒成分，例如穿孔素和颗粒酶GZMB，GNLY和KLRD1以及炎性细胞因子CCL5。以区室特异性方式进一步分析了这些CD8+T细胞的免疫细胞活化，并且在来自CBG处理的样品的CD8+T细胞中注意到增加的CD25(IL2R)表达。此外,并确认先前的报告，我们注意到CBG处理的样品中有较高的基质细胞群。
结论：我们的scRNAseq研究揭示了CBG治疗和未治疗的PRLomas在肿瘤和微环境细胞成分中的转录组特征的关键差异，并首次描述了CBG治疗后CD8T细胞的先前未知激活，这可能在CBG的杀瘤作用中起作用。
方法：通过单细胞RNA测序（scRNA-seq）分析了来自3名卡麦角林（CBG）治疗和2名初治患者的5例手术切除的泌乳素瘤，以比较细胞组成和转录景观。
结果：包括肿瘤在内的六种主要细胞群（88.2％），免疫(5.6%)，基质（4.9%），祖细胞（0.6%），增殖细胞（0.4%），观察到红细胞（0.2％）。来自CBG治疗患者的肿瘤细胞表达较低水平的调节激素分泌的基因，如SCG2，VGF，TIMP1,NNAT,和CALD1，与CBG对激素加工和分泌的抑制作用一致。有趣的是,我们还观察到CBG处理的组织中CD8+T细胞数量增加.这些细胞毒性CD8+T细胞表达杀伤颗粒成分，例如穿孔素和颗粒酶GZMB，GNLY和KLRD1以及炎性细胞因子CCL5。以区室特异性方式进一步分析了这些CD8+T细胞的免疫细胞活化，并且在来自CBG处理的样品的CD8+T细胞中注意到增加的CD25(IL2R)表达。此外,并确认先前的报告，我们注意到CBG处理的样品中有较高的基质细胞群。
结论：我们的scRNAseq研究揭示了CBG治疗和未治疗的PRLomas在肿瘤和微环境细胞成分中的转录组特征的关键差异，并首次描述了CBG治疗后CD8T细胞的先前未知激活，这可能在CBG的杀瘤作用中起作用。
