IL-12- and IL-2-induced tumor regression in a new murine model of oral squamous-cell carcinoma is promoted by expression of the CD80 co-stimulatory molecule and interferon-?

Abstract

Therapy with IL‐12 or IL‐2 induces tumor regression in only a few patients with head‐and‐neck squamous cell carcinoma (SCC), and the factors promoting responsiveness have not been well defined. In this study, we examined whether combined IL‐12 and IL‐2 therapy can induce tumor regression in a new murine model of oral SCC and determined if the anti‐tumor response is promoted by expression of the immune co‐stimulatory molecule CD80 and cytokine IFN‐γ. In CD80‐positive or ‐negative subclones of a BALB/c oral SCC line in syngeneic mice, we showed that systemic rIL‐12 alone was comparable in effectiveness to combined therapy with IL‐12 and peri‐tumoral rIL‐2, inducing complete regression of the CD80+ line B7E11‐4scid. However, therapy with these cytokines had no effect on growth of the CD80– subclone B7E3‐4scid and did not induce complete regression of the CD80+ subclone B7E11‐4scid in congenic BALB/c IFN‐γ knockout mice, indicating that expression of the CD80 co‐stimulatory molecule and IFN‐γ contributes to tumor regression. In cytokine‐treated mice that rejected the CD80+ SCC line, an increase in infiltrating CD4+ lymphocytes and apoptotic bodies within the tumor specimens was observed, and resistance to rechallenge with the same tumor was detected in 50% of recipients, consistent with an immune response. Our results provide evidence that regression of oral head‐and‐neck SCC may be induced by therapy with systemic IL‐12 and that expression of the CD80 co‐stimulatory molecule by SCC and IFN‐γ by the host promote IL‐12 induced regression of SCC. Int. J. Cancer 86:368–374, 2000. © 2000 Wiley‐Liss, Inc.

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors

“…119 Since then, other models employing alternative cell lines and their syngeneic animal counterparts have been described. [120][121][122][123] The SCC VII/SF cell line implanted subcutaneously in the C3H/HeJ mouse is still the most frequently utilized subcutaneous transplantation model.…”

“…Using this new syngeneic murine model, the combined use of these two cytokines resulted in significantly greater tumor reduction than with either cytokine alone. 123 Gleich et al transfected these transformed oral keratinocytes with a class I major histocompatibility complex gene, demonstrating decreased tumorigenesis when these transfected tumor cells were implanted subcutaneously into syngeneic BALB/c mice. 126 Advantages and disadvantages of syngeneic transplantable models.…”

“…This facilitates the examination of the complex tumor-host interactions including immune surveillance, angiogenesis, stromal-epithelial signaling, tissue invasion and metastasis. Animals are typically ready for study within 14 days after inoculation with tumor cells, 50,52,123 compared to the 10-16 weeks required for DMBA-induced hamster cheek pouch carcinogenesis, 4,5,7 and 20-24 weeks required for 4-NQO-induced rat palate carcinogenesis. 6,107 Syngeneic models do have specific limitations.…”

“…For example, several of the BALB/c syngeneic oral SCC lines described by Thomas et al form tumors that grow slowly and do not metastasize. 122,123 Although the syngeneic tumors created by the subcutaneous injection of SCC VII/SF cells into C3H/HeJ mice grow more rapidly, 126 they are still limited by their benign growth pattern, which is lacking significant local invasion and/or distant spread. 120,127 In general, these models suffer from the limitation that they do not closely mimic the characteristics of the human disease.…”

Effect of the Antibody Immunotherapy by the Anti-MUC1 Monoclonal Antibody to the Oral Squamous Cell Carcinoma in Vitro

“…Recently, various basic and clinical observations suggest that the patient's immune system plays a role in the course of oral cell cancer. In vivo tumor regression by IL-12 and IL-2, inducing CD80 expression, 5) the presence of a CD8 ϩ T-cell-mediated immune response 6) and the number of dendritic cells infiltrating the tumor are highly significant prognostic parameters. 7) These results have lead to the hypothesis that activation of the patient's immune system will enhance anti-OSCC therapy.…”