Immune cell infiltration and prognosis in colorectal cancer

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Fältnamn	Indikatorer	Metadata
000		05759nam a2200421 4500
001		oai:DiVA.org:umu-153097
003		SwePub
008		181107s2018 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
020		a 9789176019313q print
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1530972 URI
040		a (SwePub)umu
041		a engb eng
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a dok2 swepub-publicationtype
100	1	a Ling, Agnes,d 1976-u Umeå universitet,Patologi4 aut0 (Swepub:umu)agslig01
245	1 0	a Immune cell infiltration and prognosis in colorectal cancer
264	1	a Umeå :b Umeå Universitet,c 2018
300		a 50 s.
338		a electronic2 rdacarrier
490	0	a Umeå University medical dissertations,x 0346-6612 ;v 1976
520		a 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.
650	7	a LANTBRUKSVETENSKAPERx Veterinärmedicinx Medicinsk biovetenskap0 (SwePub)403012 hsv//swe
650	7	a AGRICULTURAL SCIENCESx Veterinary Sciencex Medical Bioscience0 (SwePub)403012 hsv//eng
653		a Colorectal cancer
653		a molecular subgroups
653		a immune cell infiltration
653		a immune escape
653		a prognosis
700	1	a Palmqvist, Richard,c Professoru Umeå universitet,Patologi4 ths0 (Swepub:umu)ripa0001
700	1	a Edin, Sofia,c PhD, Förste forskningsingenjöru Umeå universitet,Patologi4 ths0 (Swepub:umu)soed0001
700	1	a Li, Xingru,c MD, Post-docu Umeå universitet,Patologi4 ths0 (Swepub:umu)xili0010
700	1	a Winqvist, Ola,c Professoru Department of Medicine, Karolinska Institutet, Stockholm, Sweden4 opn
710	2	a Umeå universitetb Patologi4 org
856	4	u https://umu.diva-portal.org/smash/get/diva2:1261307/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4	u https://umu.diva-portal.org/smash/get/diva2:1261307/SPIKBLAD01.pdfy spikblad
856	4	u https://umu.diva-portal.org/smash/get/diva2:1261307/PREVIEW01.pngx Previewy preview image
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-153097

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Av författaren/redakt...: Ling, Agnes, 197 ...; Palmqvist, Richa ...; Edin, Sofia, PhD ...; Li, Xingru, MD, ...; Winqvist, Ola, P ...

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