Immunoprofiles of colorectal cancer from Lynch syndrome
(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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- author
- 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
- organization
- publishing date
- 2019
- 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
- article number
- e1515612
- publisher
- Landes Bioscience
- external identifiers
-
- scopus:85053920728
- pmid:30546958
- 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
- 2024-09-17 06:06:58
@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>}}, 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}}, keywords = {{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}}, doi = {{10.1080/2162402X.2018.1515612}}, volume = {{8}}, year = {{2019}}, }