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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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The proposed model of accelerated development of TSCC.An increased proportion of T regs, combined with decreased numbers of CD8+ and IFN-γ producing T cells, leads to decreased tumor surveillance. Greater percentage of IL-22 producing T cells suggests an increased proliferation stimulus. The overall imbalance could explain the rapidly proliferative nature of TSCC. IL-22 blockade may be an attractive candidate for targeted SCC therapy, especially in the transplant population.
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pone-0062154-g007: The proposed model of accelerated development of TSCC.An increased proportion of T regs, combined with decreased numbers of CD8+ and IFN-γ producing T cells, leads to decreased tumor surveillance. Greater percentage of IL-22 producing T cells suggests an increased proliferation stimulus. The overall imbalance could explain the rapidly proliferative nature of TSCC. IL-22 blockade may be an attractive candidate for targeted SCC therapy, especially in the transplant population.

Mentions: In summary, our findings provide strong evidence that TSCC has a unique immune microenvironment that is conducive to tumor proliferation as shown schematically in Figure 7. The aggressive nature of TSCC may result from at least two opposing forces: a) increased T regs and decreased CD8+ T cells, leading to decreased immune surveillance, and b) increased exposure to IL-22, which may provide a proliferative stimulus and accelerate tumor growth. Although further work elucidating the role of IL-22 in SCC proliferation and invasion is warranted, our study sheds light upon the possible role of IL-22 in tumorigenesis in vivo and provides important information about tumor immunity in transplant recipients. Furthermore, this study suggests that targeting the IL-22 pathway may be an important, life-saving therapeutic approach for aggressive SCCs in the transplant population.


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)

The proposed model of accelerated development of TSCC.An increased proportion of T regs, combined with decreased numbers of CD8+ and IFN-γ producing T cells, leads to decreased tumor surveillance. Greater percentage of IL-22 producing T cells suggests an increased proliferation stimulus. The overall imbalance could explain the rapidly proliferative nature of TSCC. IL-22 blockade may be an attractive candidate for targeted SCC therapy, especially in the transplant population.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062154-g007: The proposed model of accelerated development of TSCC.An increased proportion of T regs, combined with decreased numbers of CD8+ and IFN-γ producing T cells, leads to decreased tumor surveillance. Greater percentage of IL-22 producing T cells suggests an increased proliferation stimulus. The overall imbalance could explain the rapidly proliferative nature of TSCC. IL-22 blockade may be an attractive candidate for targeted SCC therapy, especially in the transplant population.
Mentions: In summary, our findings provide strong evidence that TSCC has a unique immune microenvironment that is conducive to tumor proliferation as shown schematically in Figure 7. The aggressive nature of TSCC may result from at least two opposing forces: a) increased T regs and decreased CD8+ T cells, leading to decreased immune surveillance, and b) increased exposure to IL-22, which may provide a proliferative stimulus and accelerate tumor growth. Although further work elucidating the role of IL-22 in SCC proliferation and invasion is warranted, our study sheds light upon the possible role of IL-22 in tumorigenesis in vivo and provides important information about tumor immunity in transplant recipients. Furthermore, this study suggests that targeting the IL-22 pathway may be an important, life-saving therapeutic approach for aggressive SCCs in the transplant population.

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