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Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma.

Zhang S, Fujita H, Mitsui H, Yanofsky VR, Fuentes-Duculan J, Pettersen JS, Suárez-Fariñas M, Gonzalez J, Wang CQ, Krueger JG, Felsen D, Carucci JA - PLoS ONE (2013)

Bottom Line: SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin.TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC.Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, New York, United States of America.

ABSTRACT
Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-γ producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.

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Related in: MedlinePlus

IL-22, IL-22R and downstream regulator pSTAT3 are upregulated in SCC and TSCC.Expression of (a) IL-22, (b) IL-22 Receptor (IL22R) and (c) downstream molecule Phosphorylated Signal-transducer-and-activator of transcriptase 3 (pSTAT3) were all increased in tumor tissue compared to normal skin by immunohistochemistry. Bar = 100 µm.
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pone-0062154-g005: IL-22, IL-22R and downstream regulator pSTAT3 are upregulated in SCC and TSCC.Expression of (a) IL-22, (b) IL-22 Receptor (IL22R) and (c) downstream molecule Phosphorylated Signal-transducer-and-activator of transcriptase 3 (pSTAT3) were all increased in tumor tissue compared to normal skin by immunohistochemistry. Bar = 100 µm.

Mentions: Binding of IL-22 to its receptor results in tyrosine phosphorylation of JAK and subsequent activation of downstream signal-transducer-and-activator (STAT) molecules, of which STAT-3 is the principal mediator [22], [23], [24]. Particularly, STAT-3 has been implicated in both the initiation and promotion stages of cutaneous carcinogenesis, regulating keratinocyte survival and proliferation following ultraviolet irradiation [25], [26], [27], [28].To investigate if this pathway is upregulated in SCCs, we stained SCC (n = 5), TSCC (n = 5), and normal skin (n = 5) for IL-22, IL-22 receptor and phosphorylated STAT-3 (pSTAT-3). Representative images are shown (Figure 5). We found diffuse expression of IL-22 in transplant SCC and SCC from immune competent patients. We also found increased expression of IL-22 receptor at the leading edge of the invasive front in SCC (Figure 5a); this was in contrast to TSCC, which showed diffuse IL-22 receptor expression (Figure 5b). Diffuse IL-22 receptor expression mirrored diffuse expression of Ki67 expression in TSCC (Figure 1). pSTAT-3 is increased in all tumor samples compared to normal skin (Figure 5c).


Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma.

Zhang S, Fujita H, Mitsui H, Yanofsky VR, Fuentes-Duculan J, Pettersen JS, Suárez-Fariñas M, Gonzalez J, Wang CQ, Krueger JG, Felsen D, Carucci JA - PLoS ONE (2013)

IL-22, IL-22R and downstream regulator pSTAT3 are upregulated in SCC and TSCC.Expression of (a) IL-22, (b) IL-22 Receptor (IL22R) and (c) downstream molecule Phosphorylated Signal-transducer-and-activator of transcriptase 3 (pSTAT3) were all increased in tumor tissue compared to normal skin by immunohistochemistry. Bar = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646982&req=5

pone-0062154-g005: IL-22, IL-22R and downstream regulator pSTAT3 are upregulated in SCC and TSCC.Expression of (a) IL-22, (b) IL-22 Receptor (IL22R) and (c) downstream molecule Phosphorylated Signal-transducer-and-activator of transcriptase 3 (pSTAT3) were all increased in tumor tissue compared to normal skin by immunohistochemistry. Bar = 100 µm.
Mentions: Binding of IL-22 to its receptor results in tyrosine phosphorylation of JAK and subsequent activation of downstream signal-transducer-and-activator (STAT) molecules, of which STAT-3 is the principal mediator [22], [23], [24]. Particularly, STAT-3 has been implicated in both the initiation and promotion stages of cutaneous carcinogenesis, regulating keratinocyte survival and proliferation following ultraviolet irradiation [25], [26], [27], [28].To investigate if this pathway is upregulated in SCCs, we stained SCC (n = 5), TSCC (n = 5), and normal skin (n = 5) for IL-22, IL-22 receptor and phosphorylated STAT-3 (pSTAT-3). Representative images are shown (Figure 5). We found diffuse expression of IL-22 in transplant SCC and SCC from immune competent patients. We also found increased expression of IL-22 receptor at the leading edge of the invasive front in SCC (Figure 5a); this was in contrast to TSCC, which showed diffuse IL-22 receptor expression (Figure 5b). Diffuse IL-22 receptor expression mirrored diffuse expression of Ki67 expression in TSCC (Figure 1). pSTAT-3 is increased in all tumor samples compared to normal skin (Figure 5c).

Bottom Line: SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin.TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC.Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, New York, United States of America.

ABSTRACT
Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-γ producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.

Show MeSH
Related in: MedlinePlus