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. 2003 Sep 1;198(5):747-55.
doi: 10.1084/jem.20021282.

The distinct contributions of murine T cell receptor (TCR)gammadelta+ and TCRalphabeta+ T cells to different stages of chemically induced skin cancer

Michael Girardi  1 , Earl Glusac, Renata B Filler, Scott J Roberts, Iva Propperova, Julia Lewis, Robert E Tigelaar, Adrian C Hayday
Affiliations

The distinct contributions of murine T cell receptor (TCR)gammadelta+ and TCRalphabeta+ T cells to different stages of chemically induced skin cancer

Michael Girardi et al. J Exp Med. .

Abstract

Epithelial tissues in which carcinomas develop often contain systemically derived T cell receptor (TCR)alphabeta+ cells and resident intraepithelial lymphocytes that are commonly enriched in TCRgammadelta+ cells. Recent studies have demonstrated that gammadelta cells protect the host against chemically induced cutaneous malignancy, but the role of alphabeta T cells has been enigmatic, with both protective and tumor-enhancing contributions being reported in different systems. This study aims to clarify the contributions of each T cell type to the regulation of squamous cell carcinoma induced in FVB mice by a two-stage regimen of 7,12-dimethylbenz[a]anthracene initiation followed by repetitive application of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate. This protocol permits one to monitor the induction of papillomas and the progression of those papillomas to carcinomas. The results show that whereas gammadelta cells are strongly protective, the nonredundant contributions of alphabeta T cells to the host's protection against papillomas are more modest. Furthermore, at both high and low doses of carcinogens, alphabeta T cells can contribute to rather than inhibit the progression of papillomas to carcinomas. As is likely to be the case in humans, this study also shows that the contribution of T cells to tumor immunosurveillance is regulated by modifier genes.

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Figures

Figure 1.
Figure 1.
Rapid tumor onset and increased tumor incidence in TCRδ−/− and TCRβ2/2δ2/2 mice. Under a two-stage chemical carcinogenesis protocol of initiation with 200 nmol DMBA and weekly application of (low dose) 5 nmol TPA, WT (w.t.) and T cell–deficient mice were followed for the development of all cutaneous tumors (papillomas or carcinomas >1 mm; see Fig. 2 and Table II for breakdown). Although TCRβ−/− mice (deficient in only αβ T cells) showed no significant difference in tumorigenesis relative to WT mice, TCRδ−/− mice (deficient in γδ T cells) and TCRβ−/−δ−/− mice (deficient in both αβ and γδ T cells) exhibited an earlier onset and marked increase in tumor development. *, P ≤ 0.0001 for β−/−δ−/− and δ−/− versus WT or β−/−.
Figure 2.
Figure 2.
Morphologic assessment of tumor development in T cell–deficient mice. Tumors that developed under two-stage chemical carcinogenesis (refer to Fig. 1) were scored as clinically apparent papillomas (P) or carcinomas (C), as described in Materials and Methods. (A) Hematoxylin and eosin–stained sections of representative tumors were obtained and typical examples are shown. This papilloma (P1; see text for scoring index) exhibited a symmetric outline, acanthosis, and papillomatosis (×40), with uniform keratinocytes with moderately abundant cytoplasm and small round nuclei (×100). This early carcinoma (C2) exhibited an asymmetric outline and expansion of neoplastic follicle-like structures composed of atypical epithelium (×40). There was haphazard infiltration of the dermis by pleomorphic keratinocytes with increased nuclear/cytoplasmic ratio (×100). This later stage carcinoma (C3) exhibited a poorly organized, asymmetric pattern of growth (×40) comprised of atypical keratinocytes aggregated around vascular connective tissue cores (×100). (B) Papilloma and carcinoma development for the experiment depicted in Fig. 1 at 17 wk. *, P < 0.05; **, P < 0.01; ***, P < 0.005; ****, P < 0.001. (C) Papilloma and carcinoma development in a second independent experiment at study termination. n.d., not done. (D) Tumor appearance of two representative mice from each of the TCRδ−/− and TCRβ−/−δ−/− groups.
Figure 3.
Figure 3.
Marked decrease in tumor burden and progression in TCRβ−/− mice. Under a two-stage chemical carcinogenesis protocol of initiation with 200 nmol DMBA and weekly application of (high dose) 40 nmol TPA, WT (w.t.) and TCRβ−/− mice were followed for the development of tumors (>1 mm). TCRβ−/− mice deficient in αβ T cells demonstrated a markedly lower (A) tumor area and (B) carcinoma development. (C) Clinical tumor appearance of two representative mice from each of the WT and β−/− groups. (D) Representative flow cytometric analysis for the presence of αβ+ (H57) T cells in the spleens of 6-wk-old TCRβ−/− mice, WT mice, and TCRβ−/− mice reconstituted at birth by intraperitoneal injection of day 13.5 FLHSCs. (E and F) Reconstituted TCRβ−/− mice (β−/− + αβ T cells) demonstrated a higher tumor area (E) and greater rate of carcinoma formation (F) than TCRβ−/− mice. *, P ≤ 0.02; **, P ≤ 0.01; ***, P ≤ 0.005.
Figure 4.
Figure 4.
Tumor development in crosses of susceptible FVB.TCRδ2/2 with resistant C57BL/6.TCRδ2/2 mice. FVB.TCRδ−/− (FVB.δ−/−) and C57BL/6.TCRδ−/− (B6.δ−/−) mice were bred to produce F1.δ−/−, F2.δ−/−, and (F1 × FVB) backcross (BC).δ−/− offspring. Under a two-stage chemical carcinogenesis protocol of initiation with 200 nmol DMBA and weekly application of (low dose) 5 nmol TPA, mice were followed for the development of all cutaneous tumors (papillomas or carcinomas >1 mm) at week 16 after DMBA initiation. The mean number ± standard deviation of total tumors per animal for each group is represented. Although none of the B6.δ−/− mice developed more than two tumors, 46.3% of the BC.δ−/− and 26.2% of the F2.δ2/2 mice developed more than two tumors.
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References

    1. Peto, J. 2001. Cancer epidemiology in the last century and the next decade. Nature. 411:390–395. - PubMed
    1. Pentland, A.P., J.W. Schoggins, G.A. Scott, K.N. Khan, and R. Han. 1999. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis. 20:1939–1944. - PubMed
    1. Orengo, I.F., J. Gerguis, R. Phillips, A. Guevara, A.T. Lewis, and H.S. Black. 2002. Celecoxib, a cyclooxygenase 2 inhibitor as a potential chemopreventive to UV-induced skin cancer: a study in the hairless mouse model. Arch. Dermatol. 138:751–755. - PubMed
    1. Ferguson, A. 1977. Intraepithelial lymphocytes of the small intestine. Gut. 18:921–937. - PMC - PubMed
    1. Hayday, A., E. Theodoridis, E. Ramsburg, and J. Shires. 2001. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2:997–1003. - PubMed

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