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首页> 外文学位 >A link between TGFbeta and intraepithelial tumor infiltrating lymphocytes in microsatellite instability-high colorectal cancer.
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A link between TGFbeta and intraepithelial tumor infiltrating lymphocytes in microsatellite instability-high colorectal cancer.

机译：TGFbeta和微卫星不稳定性高结直肠癌中上皮内肿瘤浸润淋巴细胞之间的联系。

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摘要

Microsatellite instability high (MSI-H) colorectal cancers (CRCs) possess such features as heavy infiltration by intraepithelial tumor infiltrating lymphocytes (iTILs), a relatively good prognosis, and truncating mutations in the type II TGFbeta receptor (TGFbetaRII). The aim of this study was to examine the possibility of a connection between these phenomena in MSI-H CRCs. Immunohistochemical analysis identified increased tumor TGFbeta expression as predictive of high iTIL counts in MSI-H CRCs but not in microsatellite stable (MSS) CRCs. Abundant iTILs were associated with longer survival times only for patients with MSS tumors. These results indicate that iTILs in MSI-H CRCs are not part of an active anti-tumor immune response. Since TGFbeta can autoinduce itself, the extent of sensitivity of TGFbetaRII deficient MSI-H CRC cell lines was determined using an inhibitor of the complementary TGFbeta type I receptor. MSI-H CRCs remained sensitive to endogenously produced TGFbeta via this receptor. However, autoinduction of TGFbeta by endogenous cytokine was not seen and seems unlikely to explain the association between high TGFbeta and iTILs. The search for an alternate signaling mechanism to account for persistent endogenous TGFbeta sensitivity led to the identification of a membrane-bound form of TGFbeta on CRC cells. This membranous-TGFbeta was able to initiate cell-cell contact dependent signaling in both adjacent CRC cells and lymphocytes, thereby representing a novel mode of paracrine tumor TGFbeta signaling. In order to explore the origin and effects of TGFbeta on CRC/iTIL interactions, a Transwell system was used allowing for basolateral migration of either peripherally- or intraepithelially-derived lymphocytes into CRC monolayers. MSI-H CRCs preferentially retained and expanded lymphocytes from the latter population and were found to induce a lesser degree of T cell activation than their MSS counterparts. TGFbeta played a modulatory, though not definitive, role in the observed CRC/lymphocyte interactions. Inferior activation by MSI-H CRCs may explain the lack of prognostic benefit conferred by iTILs within these cancers. We have thus documented within MSI-H CRCs an association between iTILs and TGFbeta which is not mediated by TGFbetaRII mutation, a lack of association between iTILs and survival, and a probable origin for iTILs within a pretolerized intraepithelial lymphocyte subset.
机译：高微卫星不稳定性（MSI-H）大肠癌（CRC）具有上皮内肿瘤浸润淋巴细胞（iTIL）大量浸润，相对较好的预后以及II型TGFbeta受体（TGFbetaRII）的突变突变等特征。这项研究的目的是检查MSI-H CRC中这些现象之间联系的可能性。免疫组织化学分析确定，肿瘤TGFbeta表达增加可预测MSI-H CRC中iTIL计数高，而微卫星稳定（MSS）CRC中则不然。仅对于MSS肿瘤患者，大量的iTIL与更长的生存时间相关。这些结果表明，MSI-H CRC中的iTIL不是主动的抗肿瘤免疫应答的一部分。由于TGFbeta可以自我诱导，因此使用I型互补TGFbeta抑制剂可确定TGFbetaRII缺陷型MSI-H CRC细胞系的敏感性程度。 MSI-H CRC通过该受体对内源产生的TGFbeta仍然敏感。但是，未见内源性细胞因子对TGFβ的自诱导作用，似乎不可能解释高TGFβ与iTIL之间的关系。寻找另一种信号机制来解释持续的内源性TGFbeta敏感性导致了对CRC细胞上TGFbeta的膜结合形式的鉴定。该膜TGFβ能够在相邻的CRC细胞和淋巴细胞中启动细胞-细胞接触依赖性信号传导，从而代表了旁分泌肿瘤TGFβ信号传导的新型模式。为了探讨TGFbeta对CRC / iTIL相互作用的起源和影响，使用了Transwell系统，可将外周或上皮内来源的淋巴细胞基底外侧迁移到CRC单层中。 MSI-H CRCs优先保留和扩增来自后者的淋巴细胞，并且发现它们诱导的T细胞活化程度低于其MSS对应物。 TGFbeta在观察到的CRC /淋巴细胞相互作用中起着调节作用，尽管不是确定的。 MSI-H CRC的亚活化可能解释了iTIL在这些癌症中缺乏预后益处。因此，我们已经在MSI-H CRC中记录了iTIL和TGFbeta之间的关联，该关联不是由TGFbetaRII突变介导的，iTIL与存活之间缺乏关联，并且是iTIL的可能耐受性是在耐受前的上皮内淋巴细胞亚群中。

著录项

  • 作者

    Baker, Kristi Dorothy.;

  • 作者单位

    McGill University (Canada).;

  • 授予单位 McGill University (Canada).;
  • 学科 Health Sciences Pathology.Health Sciences Oncology.Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 203 p.
  • 总页数 203
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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