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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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TSCC shows fewer CD8+ T cells and increased Foxp3/CD8 ratio.Representative immunohistochemistry and summary data with median cell count values of (a) CD3+ T cells (b) CD8+ T cells (c) Foxp3+ T cells in normal skin (n = 5), SCC (n = 10) and TSCC (n = 10). Each dot represents one patient. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Bar = 100 µm. Triple label immunofluorescence confirms the presence of CD4+CD25+Foxp3+ T regulatory cells (see arrows) in SCC (e) and TSCC (f). Images are presented in pseudo color: Foxp3 (red), CD4 (blue) and CD25 (green), located above merged image. Red and green overlapping cells appear yellow in color; red and blue appear purple; and green and blue appear aqua; cells labeled with all three stains appear white.
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pone-0062154-g002: TSCC shows fewer CD8+ T cells and increased Foxp3/CD8 ratio.Representative immunohistochemistry and summary data with median cell count values of (a) CD3+ T cells (b) CD8+ T cells (c) Foxp3+ T cells in normal skin (n = 5), SCC (n = 10) and TSCC (n = 10). Each dot represents one patient. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Bar = 100 µm. Triple label immunofluorescence confirms the presence of CD4+CD25+Foxp3+ T regulatory cells (see arrows) in SCC (e) and TSCC (f). Images are presented in pseudo color: Foxp3 (red), CD4 (blue) and CD25 (green), located above merged image. Red and green overlapping cells appear yellow in color; red and blue appear purple; and green and blue appear aqua; cells labeled with all three stains appear white.

Mentions: As host immunity can regulate tumor behavior, we set out to characterize the number, type, and distribution of tumor-associated T cells in the SCC and TSCC microenvironment (Figure 2). We found significantly greater numbers of CD3+ T cells associated with SCC and TSCC compared to normal skin (SCC 122.44±7.30 cells/µm2×105 and TSCC 68.73±7.38 cells/µm2×105 vs. Normal 22.56±0.73 cells/µm2×105, mean ± SEM, p<0.01; Figure 2a). There were also significantly greater numbers of CD8+ T cells associated with SCC and TSCC compared to normal skin (SCC 95.70±9.92 cells/µm2×105 and TSCC 48.22±8.38 cells/µm2×105 vs. Normal 6.88±2.56 cells/µm2×105, mean ± SEM, p<0.05; Figure 2b). Both CD3+ and CD8+ T cells were more abundant in SCC compared to TSCC. We also observed that CD3+ and CD8+ T cells predominantly aggregated in the peritumoral regions while relatively few T cells were located within tumor nests.


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)

TSCC shows fewer CD8+ T cells and increased Foxp3/CD8 ratio.Representative immunohistochemistry and summary data with median cell count values of (a) CD3+ T cells (b) CD8+ T cells (c) Foxp3+ T cells in normal skin (n = 5), SCC (n = 10) and TSCC (n = 10). Each dot represents one patient. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Bar = 100 µm. Triple label immunofluorescence confirms the presence of CD4+CD25+Foxp3+ T regulatory cells (see arrows) in SCC (e) and TSCC (f). Images are presented in pseudo color: Foxp3 (red), CD4 (blue) and CD25 (green), located above merged image. Red and green overlapping cells appear yellow in color; red and blue appear purple; and green and blue appear aqua; cells labeled with all three stains appear white.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646982&req=5

pone-0062154-g002: TSCC shows fewer CD8+ T cells and increased Foxp3/CD8 ratio.Representative immunohistochemistry and summary data with median cell count values of (a) CD3+ T cells (b) CD8+ T cells (c) Foxp3+ T cells in normal skin (n = 5), SCC (n = 10) and TSCC (n = 10). Each dot represents one patient. Asterisks (*) indicate significance, where *P<0.05, **P<0.01 and ***P<0.005. Bar = 100 µm. Triple label immunofluorescence confirms the presence of CD4+CD25+Foxp3+ T regulatory cells (see arrows) in SCC (e) and TSCC (f). Images are presented in pseudo color: Foxp3 (red), CD4 (blue) and CD25 (green), located above merged image. Red and green overlapping cells appear yellow in color; red and blue appear purple; and green and blue appear aqua; cells labeled with all three stains appear white.
Mentions: As host immunity can regulate tumor behavior, we set out to characterize the number, type, and distribution of tumor-associated T cells in the SCC and TSCC microenvironment (Figure 2). We found significantly greater numbers of CD3+ T cells associated with SCC and TSCC compared to normal skin (SCC 122.44±7.30 cells/µm2×105 and TSCC 68.73±7.38 cells/µm2×105 vs. Normal 22.56±0.73 cells/µm2×105, mean ± SEM, p<0.01; Figure 2a). There were also significantly greater numbers of CD8+ T cells associated with SCC and TSCC compared to normal skin (SCC 95.70±9.92 cells/µm2×105 and TSCC 48.22±8.38 cells/µm2×105 vs. Normal 6.88±2.56 cells/µm2×105, mean ± SEM, p<0.05; Figure 2b). Both CD3+ and CD8+ T cells were more abundant in SCC compared to TSCC. We also observed that CD3+ and CD8+ T cells predominantly aggregated in the peritumoral regions while relatively few T cells were located within tumor nests.

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