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Immunoprofiles of colorectal cancer from Lynch syndrome

Walkowska, Joanna; Kallemose, Thomas; Jönsson, Göran LU ; Jönsson, Mats LU ; Andersen, Ove; Andersen, Mads Hald; Svane, Inge Marie; Langkilde, Anne; Nilbert, Mef LU and Therkildsen, Christina LU (2019) In OncoImmunology 8(1).
Abstract

Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells,... (More)

Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
familial colorectal cancer type X, Hereditary non-polyposis colorectal cancer, immunophenotypes, microsatellite instability, mismatch repair
in
OncoImmunology
volume
8
issue
1
publisher
Landes Bioscience
external identifiers
  • scopus:85053920728
ISSN
2162-4011
DOI
10.1080/2162402X.2018.1515612
language
English
LU publication?
yes
id
408901e1-c241-4847-9461-fc2ca5eb14f4
date added to LUP
2018-10-26 09:18:39
date last changed
2019-02-20 11:33:29
@article{408901e1-c241-4847-9461-fc2ca5eb14f4,
  abstract     = {<p>Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.</p>},
  articleno    = {e1515612},
  author       = {Walkowska, Joanna and Kallemose, Thomas and Jönsson, Göran and Jönsson, Mats and Andersen, Ove and Andersen, Mads Hald and Svane, Inge Marie and Langkilde, Anne and Nilbert, Mef and Therkildsen, Christina},
  issn         = {2162-4011},
  keyword      = {familial colorectal cancer type X,Hereditary non-polyposis colorectal cancer,immunophenotypes,microsatellite instability,mismatch repair},
  language     = {eng},
  number       = {1},
  publisher    = {Landes Bioscience},
  series       = {OncoImmunology},
  title        = {Immunoprofiles of colorectal cancer from Lynch syndrome},
  url          = {http://dx.doi.org/10.1080/2162402X.2018.1515612},
  volume       = {8},
  year         = {2019},
}