title: OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer.
abstract: BACKGROUND
  OX40 is a TNF receptor family member expressed by activated T cells. Its triggering by OX40 ligand promotes lymphocyte survival and memory generation. Anti-OX40 agonistic monoclonal antibodies (mAb) are currently being tested in cancer immunotherapy. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective.
  
  
  METHODS
  OX40 gene expression was analyzed in 50 freshly excised CRC and corresponding healthy mucosa by qRT-PCR. A tissue microarray including 657 clinically annotated CRC specimens was stained with anti-OX40, -CD8 and -FOXP3 mAbs by standard immunohistochemistry. The CRC cohort was randomly split into training and validation sets. Correlations between CRC infiltration by OX40+ cells alone, or in combination with CD8+ or FOXP3+ cells, and clinical-pathological data and overall survival were comparatively evaluated.
  
  
  RESULTS
  OX40 gene expression in CRC significantly correlated with FOXP3 and CD8 gene expression. High CRC infiltration by OX40+ cells was significantly associated with favorable prognosis in training and validation sets in univariate, but not multivariate, Cox regression analysis. CRC with OX40(high)/CD8(high) infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40(low)/CD8(high), OX40(high)/CD8(low) or OX40(low)/CD8(low) infiltration in both uni- and multivariate analysis. In contrast, prognostic significance of OX40+ and FOXP3+ cell infiltration was not enhanced by a combined evaluation. Irrespective of TNM stage, CRC with OX40(high)/CD8(high) density infiltrates showed an overall survival similar to that of all stage I CRC included in the study.
  
  
  CONCLUSIONS
  OX40(high)/CD8(high) density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers.
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weixler
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cremonesi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorge
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Manuele Giuseppe
authors.initials: MG
authors.lastname: Muraro
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Tarik
authors.initials: T
authors.lastname: Delko
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Nebiker
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Däster
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Valeria
authors.initials: V
authors.lastname: Governa
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Amicarella
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.|Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Savas D
authors.initials: SD
authors.lastname: Soysal
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kettelhack
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.|IU Health Goshen Center for Cancer Care, Goshen, IN, USA.
authors.forename: Urs W
authors.initials: UW
authors.lastname: von Holzen
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.affiliation: Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.|Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Raoul A
authors.initials: RA
authors.lastname: Droeser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human
keywords: CD8; OX40; colorectal cancer; microenvironment; prognosis