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TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
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2017 (Engelska)Ingår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, nr 11, artikel-id e1356143Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.

Ort, förlag, år, upplaga, sidor
2017. Vol. 6, nr 11, artikel-id e1356143
Nyckelord [en]
TAP1, antigen presentation, colorectal cancer, immune escape, prognosis
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-142377DOI: 10.1080/2162402X.2017.1356143ISI: 000414522400004PubMedID: 29147604OAI: oai:DiVA.org:umu-142377DiVA, id: diva2:1161026
Forskningsfinansiär
Cancerfonden, CAN 2014/858Västerbottens läns landsting, VLL-463871Tillgänglig från: 2017-11-29 Skapad: 2017-11-29 Senast uppdaterad: 2018-11-13Bibliografiskt granskad
Ingår i avhandling
1. Immune cell infiltration and prognosis in colorectal cancer
Öppna denna publikation i ny flik eller fönster >>Immune cell infiltration and prognosis in colorectal cancer
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.

The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.

Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.

Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.

Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.

Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2018. s. 50
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1976
Nyckelord
Colorectal cancer, molecular subgroups, immune cell infiltration, immune escape, prognosis
Nationell ämneskategori
Medicinsk biovetenskap
Identifikatorer
urn:nbn:se:umu:diva-153097 (URN)978-91-7601-931-3 (ISBN)
Disputation
2018-11-30, E04, R-1, Norrlands Universitetssjukhus, byggnad 6E, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-11-09 Skapad: 2018-11-07 Senast uppdaterad: 2018-11-13Bibliografiskt granskad

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Ling, AgnesLöfgren-Burström, AnnaLarsson, PärLi, XingruWikberg, Maria LStenling, RogerEdin, SofiaPalmqvist, Richard

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Ling, AgnesLöfgren-Burström, AnnaLarsson, PärLi, XingruWikberg, Maria LStenling, RogerEdin, SofiaPalmqvist, Richard
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