title: Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: a multicenter phase II clinical trial.
abstract: OBJECTIVE
  To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins.
  
  
  METHODS
  Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate.
  
  
  RESULTS
  Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4+:CD8+ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4+ and a decrease of CD8+ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4+:CD8+ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls.
  
  
  CONCLUSIONS
  LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4+:CD8+ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.
authors.affiliation: National Institute of Oncology, Department of Otolaryngology and Head and Neck Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Tímár
authors.forename: Andrea
authors.initials: A
authors.lastname: Ladányi
authors.forename: Csaba
authors.initials: C
authors.lastname: Forster-Horváth
authors.forename: Júlia
authors.initials: J
authors.lastname: Lukits
authors.forename: Balázs
authors.initials: B
authors.lastname: Döme
authors.forename: Eva
authors.initials: E
authors.lastname: Remenár
authors.forename: Mária
authors.initials: M
authors.lastname: Godény
authors.forename: Miklós
authors.initials: M
authors.lastname: Kásler
authors.forename: Beáta
authors.initials: B
authors.lastname: Bencsik
authors.forename: Gábor
authors.initials: G
authors.lastname: Répássy
authors.forename: György
authors.initials: G
authors.lastname: Szabó
authors.forename: Norbert
authors.initials: N
authors.lastname: Velich
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Suba
authors.forename: János
authors.initials: J
authors.lastname: Elo
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Balatoni
authors.forename: Károly
authors.initials: K
authors.lastname: Pócza
authors.forename: Béla
authors.initials: B
authors.lastname: Zemplén
authors.forename: Paul
authors.initials: P
authors.lastname: Chretien
authors.forename: Eyal
authors.initials: E
authors.lastname: Talor
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001707:Biopsy, Needle; D016516:CD4-CD8 Ratio; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D007213:Indomethacin / Q000627:therapeutic use; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2; D003520:Cyclophosphamide; D007213:Indomethacin