title: Leukocyte infiltrate in gastrointestinal adenocarcinomas is strongly associated with tumor microsatellite instability but not with tumor immunogenicity.
abstract: OBJECTIVE
  To analyze the correlation of genomic instability with leukocyte infiltrate in gastrointestinal carcinomas (GIACs) and with tumor immunogenicity, e.g., HLA class I cell surface expression defects and galectin-3 and PDL-1 expression.
  
  
  METHODS
  Lymphocyte and macrophage infiltrations were immunohistochemically studied in HLA class I negative GIACs with sporadic high-level microsatellite instability (MSI-H) or microsatellite stability (MSS).
  
  
  RESULTS
  Tumors with MSI-H were associated with the following: dense infiltration (CD45, P < 0.001); cytotoxic CD8-positive lymphocytes (P < 0.001); and a complete absence of HLA class I cell surface expression, due to inactivating β2-microglobulin (β2-m) mutation in 50% of cases. In contrast, HLA class I negative tumors with MSS were significantly associated with fewer CD8-positive lymphocytes. There was no association between microsatellite instability and other molecular features of the tumor cells, including expression of galectin-3. Finally, macrophage infiltrate in the tumors was not correlated with microsatellite instability or HLA class I cell surface expression (CD64, P = 0.63; CD163, P = 0.51).
  
  
  CONCLUSIONS
  Microsatellite instability appears to be the most important factor determining the composition, density, and localization of leukocyte infiltrate, which is independent of other molecular features such expression of HLA class I cells, galectin-3, or programmed death ligand-1. Accordingly, the strong intratumoral CD8+ T infiltration of MSI-H tumors may be produced by elevated levels of specific inflammatory chemokines in the tumor microenvironment.
authors.affiliation: Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Avenida de las Fuerzas Armadas s/n, 18014, Granada, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bernal
authors.forename: Angel
authors.initials: A
authors.lastname: Concha
authors.forename: Pablo
authors.initials: P
authors.lastname: Sáenz-López
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Rodríguez
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabrera
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen; D015536:Down-Regulation; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000276:immunology; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D037502:Galectin 3; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin