Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.
Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.
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肺转移瘤的形态学外观、细胞外基质含量和血管密度可预测过继转移的自然杀伤细胞和 T 细胞浸润的允许程度。
DOI：
10.1007/s00262-005-0043-4
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Basse,PH
中科院分区：
文献类型：
--
作者：
Yang,Q;Goding,S;Hagenaars,M;Carlos,T;Albertsson,P;Kuppen,P;Nannmark,U;Hokland,ME;Basse,PH
我们最近已经证明，过继转移的IL-2激活的自然杀伤(A-NK)细胞能够消除公认的B16-F10.P1黑色素瘤肺转移。但部分B16-F10.P1肺转移瘤对A-NK细胞的侵袭耐受，对A-NK细胞治疗也耐受。与浸润性(I-P)转移瘤的“疏松”形态相比，耐浸润性(I-R)B16-F10.P1转移瘤具有独特的“致密”形态。在此，我们发现在小鼠Lewis肺癌(3LL)、MCA-102肉瘤和MC38结肠癌以及大鼠MADB106乳腺癌的肺转移中也发现了I-P疏松瘤和I-R致密瘤。此外，致密性肿瘤的侵袭抵抗并不局限于A-NK细胞，因为PHA和IL-2刺激的CD8+T细胞(T-LAK细胞)对致密性肿瘤的侵袭能力也很差。对肿瘤细胞外基质(ECM)成分和PECAM-1+血管系统的分析显示，I-R病变血管稀少，含有极少量的层粘连蛋白、胶原和纤维连接蛋白。相反，I-P疏松肿瘤血管丰富，含有大量的ECM成分。有趣的是，细胞外基质成分在I-P松散肿瘤中的分布模式与正常肺组织几乎相同，这表明这些肿瘤围绕着为松散肿瘤提供支持组织和丰富血液供应的肺泡壁而发展。总之，激活的NK和T细胞对肿瘤的侵袭与恶性组织中ECM成分和PECAM-1+血管系统的存在有关。因此，分析肿瘤活检组织中ECM和血管的分布可能有助于选择最有可能从细胞过继免疫治疗中受益的患者。
We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique “compact” morphology compared to the “loose” morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1+vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1+vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.