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The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C

Moussai, Dariush; Mitsui, Hiroshi; Pettersen, Julia S; Pierson, Katherine C; Shah, Kejal R; Suarez-Farinas, Mayte; Cardinale, Irma R; Bluth, Mark J; Krueger, James G; Carucci, John A
Metastases from primary cutaneous squamous cell carcinoma (SCC) account for the majority of the approximately 10,000 non-melanoma skin cancer deaths in the United States annually. We studied lymphangiogenesis in human SCC because of the potential link to metastasis. SCC samples were stained for lymphatic endothelial vessel marker LYVE-1 and positive cells were counted and compared with cells in normal skin. Gene set enrichment analysis and reverse transcription (RT)-PCR were performed on SCC, on adjacent non-tumor-bearing skin, and on normal skin to determine the differential expression of lymphangiogenesis-associated genes. Laser capture microdissection (LCM) was performed to isolate tumor cells and tumor-associated inflammatory cells for further gene expression analysis. Immunofluorescence was performed to determine the source of vascular endothelial growth factor-C (VEGF-C) in the tumor microenvironment. We found increased lymphatic density and reorganized lymphatic endothelial vessels in the dermis immediately adjacent to SCC nests. RT-PCR confirmed the presence of VEGF-C in skin immediately adjacent to SCC. LCM confirmed the increased expression of VEGF-C, the SCC inflammatory infiltrate. The presence of CD163(+)/CD68(+)/VEGFC(+) cells and absence of VEGF-C expression by CD3(+) or CD11C(+) cells suggested that VEGF-C is derived from tumor-associated macrophages. Clarification of mechanisms governing SCC-mediated lymphangiogenesis may identify potential targets for therapeutic intervention against aggressive or inoperable disease
PMID: 20827282
ISSN: 1523-1747
CID: 138272

Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients

Kosmidis, Maria; Dziunycz, Piotr; Suarez-Farinas, Mayte; Muhleisen, Beda; Scharer, Leo; Lauchli, Severin; Hafner, Jurg; French, Lars E; Schmidt-Weber, Carsten; Carucci, John A; Hofbauer, Gunther F L
Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTRs). The immune system plays a major role in the fight against SCC, however, little is known about the local inflammatory response in SCC at all. We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs. RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis. SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4, CD8, TBET, GATA-3, FOXP3, RORC, IFN-gamma, IL-4, TGF-beta, IL-10, and IL-17A mRNA expression. Immunohistochemistry was carried out in SCC for CD3, CD4, CD8, and FOXP3 expression. Considerable inflammation was seen in both patient groups. SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature. CD4(+) mRNA was diminished in immunosuppression. Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients. T-BET and IFN-gamma mRNA expression were decreased in the OTR group. Although Th17-weighted inflammation was unchanged, IL-17A mRNA level was markedly decreased with immunosuppression. Regulatory T cells, characterized by FOX-P3 and TGF-beta mRNA level, were decreased in OTRs. Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients
PMID: 20463594
ISSN: 1537-4513
CID: 114950

Poly-activated tumor-associated macrophages in cutaneous squamous cell carcinoma [Meeting Abstract]

Pettersen, JS; Fuentes-Duculan, J; Suarez-Farinas, M; Pierson, KC; Moussai, D; Bluth, MJ; Krueger, JG; Lowes, MA; Carucci, JA
ISI:000276455100321
ISSN: 0022-202x
CID: 114988

Regulatory T cells are associated with the human cutaneous SCC microenvironment and suppress activation of naive T cells stimulated by CD3/28 [Meeting Abstract]

Bluth, MJ; Pettersen, J; Suarez-Farinas, M; Moussai, D; Fuentes-Duculan, J; Krueger, JG; Carucci, JA
ISI:000276455100344
ISSN: 0022-202x
CID: 114989

Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production

Fujita, Hideki; Nograles, Kristine E; Kikuchi, Toyoko; Gonzalez, Juana; Carucci, John A; Krueger, James G
IL-22 is a cytokine that acts mainly on epithelial cells. In the skin, it mediates keratinocyte proliferation and epidermal hyperplasia and is thought to play a central role in inflammatory diseases with marked epidermal acanthosis, such as psoriasis. Although IL-22 was initially considered a Th17 cytokine, increasing evidence suggests that T helper cells can produce IL-22 even without IL-17 expression. In addition, we have shown the existence of this unique IL-22-producing T cell in normal skin and in the skin of psoriasis and atopic dermatitis patients. In the present study, we investigated the ability of cutaneous resident dendritic cells (DCs) to differentiate IL-22-producing cells. Using FACS, we isolated Langerhans cells (LCs; HLA-DR(+)CD207(+) cells) and dermal DCs (HLA-DR(hi)CD11c(+)BDCA-1(+) cells) from normal human epidermis and dermis, respectively. Both LCs and dermal DCs significantly induced IL-22-producing CD4(+) and CD8(+) T cells from peripheral blood T cells and naive CD4(+) T cells in mixed leukocyte reactions. LCs were more powerful in the induction of IL-22-producing cells than dermal DCs. Moreover, in vitro-generated LC-type DCs induced IL-22-producing cells more efficiently than monocyte-derived DCs. The induced IL-22 production was more correlated with IFN-gamma than IL-17. Surprisingly, the majority of IL-22-producing cells induced by LCs and dermal DCs lacked the expression of IL-17, IFN-gamma, and IL-4. Thus, LCs and dermal DCs preferentially induced helper T cells to produce only IL-22, possibly 'Th22' cells. Our data indicate that cutaneous DCs, especially LCs, may control the generation of distinct IL-22 producing Th22 cells infiltrating into the skin
PMCID:2799849
PMID: 19996179
ISSN: 1091-6490
CID: 114949

Myeloid dendritic cells from human cutaneous squamous cell carcinoma are poor stimulators of T-cell proliferation

Bluth, Mark J; Zaba, Lisa C; Moussai, Dariush; Suarez-Farinas, Mayte; Kaporis, Helen; Fan, Linda; Pierson, Katherine C; White, Traci R; Pitts-Kiefer, Alexander; Fuentes-Duculan, Judilyn; Guttman-Yassky, Emma; Krueger, James G; Lowes, Michelle A; Carucci, John A
To determine the phenotype and function of myeloid dendritic cells (DCs) from human cutaneous squamous-cell carcinoma (SCC), we studied their surface marker expression and allo-stimulatory potential ex vivo. There were abundant CD11c(+) myeloid DCs, as well as TNF and inducible nitric oxide synthase (iNOS)-producing DCs, in and around SCC tumor nests. Although myeloid DCs from SCC, adjacent non-tumor-bearing skin, and normal skin, were phenotypically similar by flow cytometry, and there was a pronounced genomic signature of mature DCs in SCC, they showed different T-cell stimulatory potential in an allogeneic mixed leukocyte reaction. Myeloid DCs from SCC were less potent stimulators of allogeneic T-cell proliferation than DCs from non-tumor-bearing skin. Culture with a DC-maturing cytokine cocktail (IL-1beta, IL-6, TNF-alpha, and PGE(2)) enhanced stimulatory potential in DCs from non-tumor-bearing skin, whereas SCC-associated DCs remained poor stimulators of T-cell proliferation. The microenvironment associated with SCC showed expression of TGF-beta, IL-10, and VEGF-A, factors capable of suppressing the DC function. These findings indicate that CD11c(+)/HLA-DR(hi) DCs from SCC are mature, but are not potent stimulators of T-cell proliferation compared with phenotypically similar DCs isolated from non-tumor-bearing skin. Identification of mechanisms responsible for suppression of tumor-associated DCs may provide insight into the evasion of immunosurveillance by SCC
PMCID:2846605
PMID: 19387481
ISSN: 1523-1747
CID: 114947

Selection criteria for genetic assessment of patients with familial melanoma

Leachman, Sancy A; Carucci, John; Kohlmann, Wendy; Banks, Kimberly C; Asgari, Maryam M; Bergman, Wilma; Bianchi-Scarra, Giovanna; Brentnall, Teresa; Bressac-de Paillerets, Brigitte; Bruno, William; Curiel-Lewandrowski, Clara; de Snoo, Femke A; Debniak, Tadeusz; Demierre, Marie-France; Elder, David; Goldstein, Alisa M; Grant-Kels, Jane; Halpern, Allan C; Ingvar, Christian; Kefford, Richard F; Lang, Julie; MacKie, Rona M; Mann, Graham J; Mueller, Kurt; Newton-Bishop, Julia; Olsson, Hakan; Petersen, Gloria M; Puig, Susana; Rigel, Darrell; Swetter, Susan M; Tucker, Margaret A; Yakobson, Emanuel; Zitelli, John A; Tsao, Hensin
Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing
PMCID:3307795
PMID: 19751883
ISSN: 1097-6787
CID: 114948

Immunosuppression affects CD4+mRNA and induces Th2 dominance in the inflammatory microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients [Meeting Abstract]

Dziunycz, P; Kosmidis, M; Suarez-Farinas, M; Muhleisen, B; Scharer, L; Lauchli, S; French, LE; Schmidt-Weber, C; Carucci, JA; Hofbauer, GF
ISI:000269264100438
ISSN: 0022-202x
CID: 114993

"The human cutaneous SCC microenvironment is associated with CD163+macrophages, IL-10 and MMPs 1, 3, 9, 10, 11, 13 and 14" [Meeting Abstract]

Pitts-Kiefer, A; Bluth, MJ; Fan, L; Lowes, MA; Carucci, JA
ISI:000264994000337
ISSN: 0022-202x
CID: 114990

Human cutaneous squamous cell carcinoma is associated with increased density of lymphatics in the tumor microenvironment and upregulated lymphangiogenic genes [Meeting Abstract]

Moussai, D; Mayte, S; Irma, C; Carucci, JA
ISI:000264994000338
ISSN: 0022-202x
CID: 114991