title: Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome.
abstract: 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.
authors: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
authors: Viktor H
authors: VH
authors: Koelzer
authors: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
authors: Heather
authors: H
authors: Dawson
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Emilia
authors: E
authors: Andersson
authors: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
authors: Eva
authors: E
authors: Karamitopoulou
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Giuseppe V
authors: GV
authors: Masucci
authors: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland; Clinical Pathology Division, Institute of Pathology, University of Bern, Bern, Switzerland.
authors: Alessandro
authors: A
authors: Lugli
authors: Translational Research Unit (TRU), Institute of Pathology, University of Bern, Bern, Switzerland. Electronic address: inti.zlobec@pathology.unibe.ch.
authors: Inti
authors: I
authors: Zlobec
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D015999:Multivariate Analysis; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D016016:Proportional Hazards Models; D000090063:Proto-Oncogene Mas; D016019:Survival Analysis; D000074019:T-Cell Intracellular Antigen-1; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D015395:Histocompatibility Antigens Class I; C000715470:MAS1 protein, human; D039102:Poly(A)-Binding Proteins; D000090063:Proto-Oncogene Mas; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human