title: Intratumoral recombinant human interleukin-12 administration in head and neck squamous cell carcinoma patients modifies locoregional lymph node architecture and induces natural killer cell infiltration in the primary tumor.
abstract: The objective of this study was to evaluate the histologic and immunohistopathologic effects of intratumorally given recombinant human interleukin-12 on the immune cells in the primary tumors and regional lymph nodes. Ten previously untreated patients with head and neck squamous cell carcinoma (HNSCC) were injected in the primary tumor twice to thrice, once weekly, at two dose levels of 100 or 300 ng/kg, before surgery. These patients were compared with 20 non-IL-12-treated control HNSCC patients. In the primary tumor, the number of CD56+ natural killer (NK) cells was increased in IL-12-treated patients compared with control patients. In some IL-12-treated patients, an impressive peritumoral invasion of CD20+ B cells was noticed. No differences were seen in the CD8+ or CD4+ T lymphocytes. Interestingly, major differences were apparent in the architecture of the enlarged lymph nodes of IL-12-treated patients; in particular, the distribution of B cells differed and fewer primary and secondary follicles with smaller germinal centers were observed. In addition, a decrease of dendritic cell lysosyme-associated membrane glycoprotein-positive cells in the paracortex was noted, resulting in a reduction of paracortical hyperplasia. In the lymph nodes, especially the CD56+ NK cells but also the CD8+ and CD4+ T lymphocytes, produced a high amount of IFN-gamma. Patients, irrespectively of IL-12 treatment, with a high number of CD56+ cells in the primary tumor had a better overall survival than those with a low number. In conclusion, after i.t. IL-12 treatment in HNSCC patients, the largest effect was seen on the NK cells, with a higher number in the primary tumor and a high IFN-gamma mRNA expression in the lymph nodes. Significant effects were noted on B cells, with altered lymph node architecture in every IL-12-treated patient and excessive peritumoral infiltration in some patients.
authors.affiliation: Department of Medical Oncology, UMC Nijmegen, 6500 HB Nijmegen, the Netherlands. C.vanherpen@onco.umcn.nl
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Jeroen A W M
authors.initials: JA
authors.lastname: van der Laak
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Peter C
authors.initials: PC
authors.lastname: de Wilde
authors.forename: Michiel G J
authors.initials: MG
authors.lastname: Balvers
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Pieter H M
authors.initials: PH
authors.lastname: De Mulder
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019002:CD56 Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000033:anatomy & histology* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D019002:CD56 Antigen; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma