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Immune cell infiltration and prognosis in colorectal cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2018. , p. 50
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1976
Keywords [en]
Colorectal cancer, molecular subgroups, immune cell infiltration, immune escape, prognosis
National Category
Medical Bioscience
Identifiers
URN: urn:nbn:se:umu:diva-153097ISBN: 978-91-7601-931-3 (print)OAI: oai:DiVA.org:umu-153097DiVA, id: diva2:1261307
Public defence
2018-11-30, E04, R-1, Norrlands Universitetssjukhus, byggnad 6E, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2018-11-09 Created: 2018-11-07 Last updated: 2018-11-13Bibliographically approved
List of papers
1. The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues
Open this publication in new window or tab >>The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues
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2014 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 10, p. 2551-2559Article in journal (Refereed) Published
Abstract [en]

Background: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).

Methods: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).

Results: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P < 0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P < 0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis.

Conclusions: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
colorectal cancer, molecular subgroups, lymphocyte subsets, FOXP3, CD8, intratumoural subsites, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-90434 (URN)10.1038/bjc.2014.161 (DOI)000336250000021 ()24675384 (PubMedID)2-s2.0-84900542868 (Scopus ID)
Available from: 2014-07-09 Created: 2014-06-23 Last updated: 2018-11-13Bibliographically approved
2. The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer
Open this publication in new window or tab >>The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer
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2016 (English)In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, p. 21-31Article in journal (Refereed) Published
Abstract [en]

Giving strong prognostic information, T-cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T-bet may be a valuable marker in the clinical setting. Our results also indicate that T-bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keywords
colorectal cancer, Th1 lymphocytes, intratumoural subsites, molecular subgroups, BRAF, KRAS, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-121095 (URN)10.1002/cjp2.31 (DOI)000410840100003 ()27499912 (PubMedID)2-s2.0-85031719249 (Scopus ID)
Funder
Swedish Cancer Society, CAN2011/839Swedish Research Council, B03488901
Note

Ytterligare finansiärer:

Cancer Research Foundation in Northern Sweden (LP 12-1959 SE)

Syskonen Svenssons Foundation for Medical Research (2014 SE)

Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2023-03-24Bibliographically approved
3. TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
Open this publication in new window or tab >>TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed) 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.

Keywords
TAP1, antigen presentation, colorectal cancer, immune escape, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142377 (URN)10.1080/2162402X.2017.1356143 (DOI)000414522400004 ()29147604 (PubMedID)2-s2.0-85029414281 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2014/858Västerbotten County Council, VLL-463871
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2023-03-23Bibliographically approved

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