title: TIA-1 cytotoxic granule-associated RNA binding protein improves the prognostic performance of CD8 in mismatch repair-proficient colorectal cancer.
abstract: BACKGROUND
  Evidence suggests a confounding effect of mismatch repair (MMR) status on immune response in colorectal cancer. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed.
  
  
  RESULTS
  Colorectal cancers from a test (n=1197) and external validation (n=209) cohort of MMR-proficient colorectal cancers were mounted onto single and multiple punch tissue microarrays. Immunohistochemical quantification (score 0-3) was performed for CD3, CD4, CD8, CD45RO, CD68, CD163, FoxP3, GranzymeB, iNOS, mast cell tryptase, MUM1, PD1 and TIA-1 tumor-infiltrating (TILs) reactive cells. Coexpression experiments on fresh colorectal cancer specimens using specific cell population markers were performed. In the test group, higher numbers of CD3+ (p<0.001), CD4+ (p=0.029), CD8+ (p<0.001), CD45RO+ (p=0.048), FoxP3+ (p<0.001), GranzymeB+ (p<0.001), iNOS+ (p=0.035), MUM1+ (p=0.014), PD1+ (p=0.034) and TIA-1+ TILs (p<0.001) were linked to favourable outcome. Adjusting for age, gender, TNM stage and post-operative therapy, higher CD8+ (p<0.001; HR (95%CI): 0.66 (0.64-0.68)) and TIA-1+ (p<0.001; HR (95%CI): 0.56 (0.5-0.6)) were independent prognostic factors. Moreover, among patients with CD8+ infiltrates, TIA-1 further stratified 355 (35.6%) patients into prognostic subgroups (p<0.001; HR (95%CI): 0.89 (95%CI: 0.8-0.9)). Results were confirmed on the validation cohort (p=0.006). TIA-1+ cells were mostly CD8+ (57%), but also stained for TCRγδ (22%), CD66b (13%) and only rarely for CD4+, macrophage and NK cell markers.
  
  
  CONCLUSIONS
  TIA-1 adds prognostic information to TNM stage and adjuvant therapy in MMR-proficient colorectal cancer patients. The prognostic effect of CD8+ TILs is confounded by the presence of TIA-1+ which translates into improved risk stratification for approximately 35% of all patients with MMR-proficient colorectal cancers.
authors.affiliation: Institute for Pathology, University of Basel, Basel, Switzerland. izlobec@uhbs.ch
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.forename: Manuele Giuseppe
authors.initials: MG
authors.lastname: Muraro
authors.forename: Giulio
authors.initials: G
authors.lastname: Spagnoli
authors.forename: Kristi
authors.initials: K
authors.lastname: Baker
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
mesh_terms: D020137:Base Pair Mismatch; D016827:CD8 Antigens / Q000096:biosynthesis*; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004260:DNA Repair; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007107:Immune System; D020411:Oligonucleotide Array Sequence Analysis; D039102:Poly(A)-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D016827:CD8 Antigens; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human