Journal article
Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome.
- Koelzer VH Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
- Dawson H Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
- Andersson E Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Karamitopoulou E Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
- Masucci GV Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Lugli A Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
- Zlobec I Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland. Electronic address: inti.zlobec@pathology.unibe.ch.
- 2015-03-24
Published in:
- Translational research : the journal of laboratory and clinical medicine. - 2015
Adjuvants, Immunologic
CD8-Positive T-Lymphocytes
Colorectal Neoplasms
Female
Histocompatibility Antigens Class I
Humans
Male
Middle Aged
Monitoring, Immunologic
Multivariate Analysis
Poly(A)-Binding Proteins
Proportional Hazards Models
Survival Analysis
T-Cell Intracellular Antigen-1
Treatment Outcome
Tumor Microenvironment
English
Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.
- Language
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- English
- Open access status
- closed
- Identifiers
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- DOI 10.1016/j.trsl.2015.02.008
- PMID 25797890
- Persistent URL
- https://sonar.ch/global/documents/155202
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