Infiltration of CD8+ T cells into tumor cell clusters in triple-negative breast cancer
Infiltration of CD8+ T cells into tumor cell clusters in triple-negative breast cancer
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DOI：
10.1073/pnas.1817652116
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发表时间：
2019-02-26
影响因子：
11.1
通讯作者：
Levine, Herbert
中科院分区：
文献类型：
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作者：
Li, Xuefei;Gruosso, Tina;Levine, Herbert
CD 8（+）T淋巴细胞浸润到实体瘤中与各种类型癌症的良好预后相关，包括三阴性乳腺癌（TNBC）。然而，不同的渗透水平的机制基本上是未知的。在这里，我们已经表征了TNBC患者样品中核心和边缘区域中肿瘤细胞簇（紧密连接的肿瘤细胞）周围的CD 8（+）T细胞的空间分布。我们发现，在某些患者中，CD 8（+）T细胞密度在从肿瘤细胞簇的边界移动时首先降低，然后在接近中心时再次升高。为了解释各种渗透概况，我们通过偏微分方程模拟了T细胞密度的动态。我们在空间上调节T细胞的扩散/趋化系数（以模仿物理屏障）或引入扩散T细胞化学排斥剂的局部分泌。结合空间轮廓分析和建模导致支持第二个想法; i。例如，肿瘤细胞团内可能存在一种化学排斥剂，阻止CD 8（+）T细胞向肿瘤细胞团内浸润。这一结论与对胶原纤维性质的研究一致，该研究表明促结缔组织增生成分的变化并不限制CD 8（+）T淋巴细胞的浸润，因为我们没有观察到T细胞浸润水平与纤维性质之间的显著相关性。我们的工作提供了证据表明，CD 8（+）T细胞可以穿过典型的纤维化屏障，因此它们浸润到肿瘤簇中是由其他机制控制的，可能涉及局部排斥。
Infiltration of CD8(+) T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including triple-negative breast cancer (TNBC). However, the mechanisms underlying different infiltration levels are largely unknown. Here, we have characterized the spatial profile of CD8(+) T cells around tumor cell clusters (tightly connected tumor cells) in the core and margin regions in TNBC patient samples. We found that in some patients, the CD8(+) T cell density first decreases when moving in from the boundary of the tumor cell clusters and then rises again when approaching the center. To explain various infiltration profiles, we modeled the dynamics of T cell density via partial differential equations. We spatially modulated the diffusion/chemotactic coefficients of T cells (to mimic physical barriers) or introduced the localized secretion of a diffusing T cell chemorepellent. Combining the spatial-profile analysis and the modeling led to support for the second idea; i. e., there exists a possible chemorepellent inside tumor cell clusters, which prevents CD8(+) T cells from infiltrating into tumor cell clusters. This conclusion was consistent with an investigation into the properties of collagen fibers which suggested that variations in desmoplastic elements does not limit infiltration of CD8(+) T lymphocytes, as we did not observe significant correlations between the level of T cell infiltration and fiber properties. Our work provides evidence that CD8(+) T cells can cross typical fibrotic barriers and thus their infiltration into tumor clusters is governed by other mechanisms possibly involving a local repellent.