Katarzyna Stasiak, Aaron D Stevens, Ashley C Bolte, Colleen T Curley, Mirna Perusina Lanfranca, Robin S Lindsay, Ukpong B Eyo, John R Lukens, Richard J Price, Timothy N J Bullock, Victor H Engelhard
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引用次数: 0
Abstract
Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen+ myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen+ myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor.
与颅外转移患者相比,转移性脑黑色素瘤(MBM)患者的存活期更短,而这与功能失调的 CD8 T 细胞比例较高有关。本研究的目的是了解T细胞功能障碍在MBM中的根本原因。为此,我们比较了植入颅内(IC)或皮下(SC)的小鼠 B16 黑色素瘤。CD8 T 细胞活化没有改变,但在 IC 肿瘤中的代表性较低。转移的活化或天真 CD8 T 细胞在两种肿瘤中积累的数量相似,这表明血管不会对 T 细胞的存在造成不同程度的影响。令人惊讶的是,我们没有在SC或IC肿瘤小鼠的引流淋巴结中发现T细胞活化的证据,这与获得肿瘤抗原的树突状细胞(DC)表现出不成熟表型的事实一致。相反,T细胞活化发生在两种肿瘤内,在肿瘤内发现了大多数肿瘤抗原+髓系细胞。虽然瘤内DC的数量相当,但IC肿瘤中的DC获得的肿瘤抗原较少,而且是根据MHCII的上调而非CD86的上调成熟的。此外,在 IC 肿瘤中,肿瘤抗原+髓系细胞的最大群体是小胶质细胞。但是,它们的存在既不影响抗原的获得,也不影响其他髓系细胞群的表型。总之,我们的数据表明,CD8 T 细胞在 IC 肿瘤中的代表性降低是另类成熟的 DC 和/或小胶质细胞诱导出明显活化的 T 细胞的结果,这些 T 细胞最终无法继续在肿瘤内聚集。
期刊介绍:
Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions.
The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.