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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 increased Tc22 and decreased Th1 polarization.T cell “crawl outs” were activated and intracellular cytokines stained. Live CD3+CD4+ and CD3+CD8+ cells were gated, and then frequencies of the cells producing indicated cytokines were analyzed. (a) Representative dot plot analysis of IFN-γ, IL-4, IL-17, and IL-22 expression in CD4+ and CD8+ T cells from SCC specimens. Numbers indicate percent gated cells. (b) Summary results from 20 SCC and 12 TSCC patients. The Mann-Whitney U-test was used for the statistical comparison between two groups. Asterisks (*) indicate statistical significance (p<0.05).
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pone-0062154-g003: TSCC shows increased Tc22 and decreased Th1 polarization.T cell “crawl outs” were activated and intracellular cytokines stained. Live CD3+CD4+ and CD3+CD8+ cells were gated, and then frequencies of the cells producing indicated cytokines were analyzed. (a) Representative dot plot analysis of IFN-γ, IL-4, IL-17, and IL-22 expression in CD4+ and CD8+ T cells from SCC specimens. Numbers indicate percent gated cells. (b) Summary results from 20 SCC and 12 TSCC patients. The Mann-Whitney U-test was used for the statistical comparison between two groups. Asterisks (*) indicate statistical significance (p<0.05).

Mentions: We were interested in T cell polarization in TSCC vs. SCC. Th1 cells, of which IFN-γ+ secreting CD4+ cells are a prototypic example, are known to play a role in anti-tumor immunity [21]. In contrast, IL-22 producing T cells (Th22 or Tc22) can support keratinocyte proliferation and potentially accelerate tumor growth. TSCC has been associated with a Th2 phenotype while keratinocyte proliferation in psoriasis has been linked to Th17 and Th22 phenotype. Thus, Th1, Th2, Th17, Th22 and CD8+ IFN-γ and IL-22 producing T cells might all be important in the TSCC environment. Thus, we evaluated the percentages of Th1 (IFN-γ+/IL-17−), Th2 (IL-4+), Th17 (IL-17+) and Th22 (IL-22+/IL-17−) CD4+ and CD8+ cells from 20 SCC and 12 TSCC explants We collected T cell “crawl-outs” from SCC explants. While, the percentages of Th2 and Th17 cells were comparable in SCC and TSCC, we found that TSCC was associated with an increased percentage of IL-22 producing CD8+ T cells (TSCC 4.2% ±1.2% vs. SCC 2.2% ±0.75%, p<0.05) and decreased numbers of CD4+ Th1 T cells (TSCC 15.1% ±2.3% vs. SCC 25.1% ±3.2%, p<0.05; Figure 3). The decreased percentage of Th1 cells may skew the balance of pro- and anti-tumor forces toward a “tumor permissive” environment. Increased IL-22 producing cells might contribute to enhanced proliferation of TSCC.


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 increased Tc22 and decreased Th1 polarization.T cell “crawl outs” were activated and intracellular cytokines stained. Live CD3+CD4+ and CD3+CD8+ cells were gated, and then frequencies of the cells producing indicated cytokines were analyzed. (a) Representative dot plot analysis of IFN-γ, IL-4, IL-17, and IL-22 expression in CD4+ and CD8+ T cells from SCC specimens. Numbers indicate percent gated cells. (b) Summary results from 20 SCC and 12 TSCC patients. The Mann-Whitney U-test was used for the statistical comparison between two groups. Asterisks (*) indicate statistical significance (p<0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062154-g003: TSCC shows increased Tc22 and decreased Th1 polarization.T cell “crawl outs” were activated and intracellular cytokines stained. Live CD3+CD4+ and CD3+CD8+ cells were gated, and then frequencies of the cells producing indicated cytokines were analyzed. (a) Representative dot plot analysis of IFN-γ, IL-4, IL-17, and IL-22 expression in CD4+ and CD8+ T cells from SCC specimens. Numbers indicate percent gated cells. (b) Summary results from 20 SCC and 12 TSCC patients. The Mann-Whitney U-test was used for the statistical comparison between two groups. Asterisks (*) indicate statistical significance (p<0.05).
Mentions: We were interested in T cell polarization in TSCC vs. SCC. Th1 cells, of which IFN-γ+ secreting CD4+ cells are a prototypic example, are known to play a role in anti-tumor immunity [21]. In contrast, IL-22 producing T cells (Th22 or Tc22) can support keratinocyte proliferation and potentially accelerate tumor growth. TSCC has been associated with a Th2 phenotype while keratinocyte proliferation in psoriasis has been linked to Th17 and Th22 phenotype. Thus, Th1, Th2, Th17, Th22 and CD8+ IFN-γ and IL-22 producing T cells might all be important in the TSCC environment. Thus, we evaluated the percentages of Th1 (IFN-γ+/IL-17−), Th2 (IL-4+), Th17 (IL-17+) and Th22 (IL-22+/IL-17−) CD4+ and CD8+ cells from 20 SCC and 12 TSCC explants We collected T cell “crawl-outs” from SCC explants. While, the percentages of Th2 and Th17 cells were comparable in SCC and TSCC, we found that TSCC was associated with an increased percentage of IL-22 producing CD8+ T cells (TSCC 4.2% ±1.2% vs. SCC 2.2% ±0.75%, p<0.05) and decreased numbers of CD4+ Th1 T cells (TSCC 15.1% ±2.3% vs. SCC 25.1% ±3.2%, p<0.05; Figure 3). The decreased percentage of Th1 cells may skew the balance of pro- and anti-tumor forces toward a “tumor permissive” environment. Increased IL-22 producing cells might contribute to enhanced proliferation of TSCC.

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