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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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Transplant associated SCC (TSCC) shows diffuse Ki-67 staining and increased numbers of Ki-67+ cells.Representative immunohistochemistry at (a) 10X and (b) 20X, with (c) mean cell count values of Ki-67+ cells in SCC (n = 5) and TSCC (n = 5). T indicates tumor. Only cells along or within tumors were counted. Asterisks (*) indicate statistical significance, where *P<0.05. Bar = 100 µm. (d) Ki-67 (red) did not colocalize with CD3 (green) in SCC and TSCC. (e) Intracytoplasmic staining of CK5/6 (red) colocalizes with intranuclear staining of KI-67(green).
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pone-0062154-g001: Transplant associated SCC (TSCC) shows diffuse Ki-67 staining and increased numbers of Ki-67+ cells.Representative immunohistochemistry at (a) 10X and (b) 20X, with (c) mean cell count values of Ki-67+ cells in SCC (n = 5) and TSCC (n = 5). T indicates tumor. Only cells along or within tumors were counted. Asterisks (*) indicate statistical significance, where *P<0.05. Bar = 100 µm. (d) Ki-67 (red) did not colocalize with CD3 (green) in SCC and TSCC. (e) Intracytoplasmic staining of CK5/6 (red) colocalizes with intranuclear staining of KI-67(green).

Mentions: Solid organ transplant recipients are at increased risk for developing cutaneous SCC. SCCs in this group of patients tend to be more numerous, more aggressive and also has increased propensity to grow more rapidly. [19]. Transplant patients included in the study presented met criteria for catastrophic carcinomatosis defined by Berg and Otley in 2002 [3] to include (1) severe field disease; or (2) >10 SCCs excised in a one year time period, or history of in transit, regional or distant metastatic disease. Thus, these patients represented transplant recipients with the most severe skin cancer burden. All tumors specimens evaluate were obtained from AJCC Stage 1 primary cutaneous SCC. [20] We performed immunohistochemical staining for Ki-67, a marker for proliferation, to assess the proliferative rate of SCC versus TSCC. Both SCC and TSCC showed significant proliferative activity (Figure 1a and b). We found that Ki-67 expression is increased approximately 2-fold in TSCC as compared to SCC (55.08±7.3 cells/µm2×105 versus 30.12±7.1 cells/µm2×105 mean ± SEM p<0.05; Figure 1c). Notably, the pattern of Ki-67 expression was also different between these two groups. In SCC, Ki-67+ cells were present along the periphery of tumor nests, i.e. the leading edge of the carcinoma. In contrast, transplant associated SCCs not only showed positivity at the invasive edge; they also demonstrated Ki-67 positivity in aggregates within the tumor (arrows). Double label immunofluorescence showed Ki-67 was positive for the nucleus of cytokeratin 5/6 (CK5/6) positive cancer cells but not CD3 positive cells (Figure 1e and 1d); suggesting proliferating cells are keratinocytes rather than immune cells.


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)

Transplant associated SCC (TSCC) shows diffuse Ki-67 staining and increased numbers of Ki-67+ cells.Representative immunohistochemistry at (a) 10X and (b) 20X, with (c) mean cell count values of Ki-67+ cells in SCC (n = 5) and TSCC (n = 5). T indicates tumor. Only cells along or within tumors were counted. Asterisks (*) indicate statistical significance, where *P<0.05. Bar = 100 µm. (d) Ki-67 (red) did not colocalize with CD3 (green) in SCC and TSCC. (e) Intracytoplasmic staining of CK5/6 (red) colocalizes with intranuclear staining of KI-67(green).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646982&req=5

pone-0062154-g001: Transplant associated SCC (TSCC) shows diffuse Ki-67 staining and increased numbers of Ki-67+ cells.Representative immunohistochemistry at (a) 10X and (b) 20X, with (c) mean cell count values of Ki-67+ cells in SCC (n = 5) and TSCC (n = 5). T indicates tumor. Only cells along or within tumors were counted. Asterisks (*) indicate statistical significance, where *P<0.05. Bar = 100 µm. (d) Ki-67 (red) did not colocalize with CD3 (green) in SCC and TSCC. (e) Intracytoplasmic staining of CK5/6 (red) colocalizes with intranuclear staining of KI-67(green).
Mentions: Solid organ transplant recipients are at increased risk for developing cutaneous SCC. SCCs in this group of patients tend to be more numerous, more aggressive and also has increased propensity to grow more rapidly. [19]. Transplant patients included in the study presented met criteria for catastrophic carcinomatosis defined by Berg and Otley in 2002 [3] to include (1) severe field disease; or (2) >10 SCCs excised in a one year time period, or history of in transit, regional or distant metastatic disease. Thus, these patients represented transplant recipients with the most severe skin cancer burden. All tumors specimens evaluate were obtained from AJCC Stage 1 primary cutaneous SCC. [20] We performed immunohistochemical staining for Ki-67, a marker for proliferation, to assess the proliferative rate of SCC versus TSCC. Both SCC and TSCC showed significant proliferative activity (Figure 1a and b). We found that Ki-67 expression is increased approximately 2-fold in TSCC as compared to SCC (55.08±7.3 cells/µm2×105 versus 30.12±7.1 cells/µm2×105 mean ± SEM p<0.05; Figure 1c). Notably, the pattern of Ki-67 expression was also different between these two groups. In SCC, Ki-67+ cells were present along the periphery of tumor nests, i.e. the leading edge of the carcinoma. In contrast, transplant associated SCCs not only showed positivity at the invasive edge; they also demonstrated Ki-67 positivity in aggregates within the tumor (arrows). Double label immunofluorescence showed Ki-67 was positive for the nucleus of cytokeratin 5/6 (CK5/6) positive cancer cells but not CD3 positive cells (Figure 1e and 1d); suggesting proliferating cells are keratinocytes rather than immune cells.

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