title: CD8+ and FOXP3+ tumor-infiltrating T cells before and after chemoradiotherapy for rectal cancer.
abstract: BACKGROUND
  CD8+ cytotoxic T cells and forkhead box P3 (FOXP3)+ regulatory T cells are major players in tumor immunity. Increased CD8+ tumor-infiltrating lymphocytes (TILs) and high CD8/FOXP3 TIL ratios are associated with improved survival. Neoadjuvant chemoradiotherapy (CRT) can result in tumor regression; however, immunomodulation during CRT for rectal cancer has not been thoroughly assessed. We investigated whether neoadjuvant CRT altered the in situ immune cell population and clinical implications of TIL accumulation before and after CRT.
  
  
  METHODS
  We recruited 93 rectal cancer patients who underwent neoadjuvant CRT and radical resection. Pretreatment biopsy and post-CRT resected specimens were immunostained for CD8 and FOXP3, and the densities of stromal (STL) and intraepithelial (IEL) immunopositive TILs were determined separately. In addition, 54 patients with resections but without neoadjuvant CRT were enrolled for comparison.
  
  
  RESULTS
  CD8+ STL density doubled after CRT (average counts: 92 vs. 230 per microscopic field using a 20 × objective lens; P < 0.0001), whereas FOXP3+ STL counts remained stable (109 vs. 109). Compared with non-CRT cases, CRT increased CD8+ STL density. Multivariate analyses demonstrated that high post-CRT CD8 + STL density was associated with better prognosis (5-year recurrence-free survival: 87.5 vs. 57.8 %; P = 0.0058) and that a high pretreatment CD8/FOXP3 IEL ratio was a predictor of favorable tumor regression (P = 0.0029).
  
  
  CONCLUSIONS
  Favorable anticancer immunity occurred after CRT for rectal cancer by altering TIL subsets. A high CD8/FOXP3 IEL ratio before CRT and a high CD8+ STL density after CRT were associated with a favorable clinical outcome.
authors.affiliation: Department of Surgery, National Defense Medical College, Saitama, Japan, eiji-c@zf6.so-net.ne.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shinto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hase
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Hashiguchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Sekizawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shikina
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kajiwara
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Megumi
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Junji
authors.initials: J
authors.lastname: Yamamoto
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D059248:Chemoradiotherapy; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D015588:Observer Variation; D011379:Prognosis; D012004:Rectal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D005641:Tegafur / Q000627:therapeutic use; D014498:Uracil / Q000627:therapeutic use
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005641:Tegafur; D014498:Uracil