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• W2027554407 abstract "Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209+ DCs in RCCs was found to be associated with an unfavorable TH1 cell balance in the tissue and advanced tumor stages. The CD209+ DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for TH1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC. Tissue dendritic cells (DCs) may influence the progression of renal cell carcinoma (RCC) by regulating the functional capacity of antitumor effector cells. DCs and their interaction with T cells were analyzed in human RCC and control kidney tissues. The frequency of CD209+ DCs in RCCs was found to be associated with an unfavorable TH1 cell balance in the tissue and advanced tumor stages. The CD209+ DCs in RCC were unusual because most of them co-expressed macrophage markers (CD14, CD163). The phenotype of these enriched-in-renal-carcinoma DCs (ercDCs) could be reiterated in vitro by carcinoma-secreted factors (CXCL8/IL-8, IL-6, and vascular endothelial growth factor). ErcDCs resembled conventional DCs in costimulatory molecule expression and antigen cross-presentation. They did not suppress cognate cytotoxic T-lymphocyte function and did not cause CD3ζ down-regulation, FOXP3 induction, or T-cell apoptosis in situ or in vitro; thus, they are different from classic myeloid-derived suppressor cells. ErcDCs secreted high levels of metalloproteinase 9 and used T-cell crosstalk to increase tumor-promoting tumor necrosis factor α and reduce chemokines relevant for TH1-polarized lymphocyte recruitment. This modulation of the tumor environment exerted by ercDCs suggests an immunologic mechanism by which tumor control can fail without involving cytotoxic T-lymphocyte inhibition. Pharmacologic targeting of the deviated DC differentiation could improve the efficacy of immunotherapy against RCC. The mononuclear infiltrate in renal cell carcinoma (RCC) has been associated with the immunogenic nature of this tumor type and the clinical response rates achieved with immunotherapy.1Vogelzang N.J. Stadler W.M. Kidney cancer.Lancet. 1998; 352: 1691-1696Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 2Atkins M.B. Regan M. McDermott D. Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma.Clin Cancer Res. 2004; 10: 6342S-6346SCrossref PubMed Scopus (129) Google Scholar Paradoxically, the mononuclear cell infiltrate has also been negatively correlated with prognosis,3Webster W.S. Lohse C.M. Thompson R.H. Dong H. Frigola X. Dicks D.L. Sengupta S. Frank I. Leibovich B.C. Blute M.L. Cheville J.C. Kwon E.D. Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival.Cancer. 2006; 107: 46-53Crossref PubMed Scopus (61) Google Scholar suggesting limitations in the functional capability of the natural immune infiltrate to control tumor growth. Potential immune parameters that contribute to this phenomenon include the composition of the infiltrate, such as type and number of effector cells [T cells, natural killer (NK) cells, dendritic cells (DCs)], and the presence of regulatory cells (T-regulatory cells, macrophages, and myeloid-derived suppressor cells).4Schleypen J.S. Baur N. Kammerer R. Nelson P.J. Rohrmann K. Grone E.F. Hohenfellner M. Haferkamp A. Pohla H. Schendel D.J. Falk C.S. Noessner E. Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma.Clin Cancer Res. 2006; 12: 718-725Crossref PubMed Scopus (119) Google Scholar, 5Frankenberger B. Noessner E. Schendel D.J. Immune suppression in renal cell carcinoma.Semin Cancer Biol. 2007; 17: 330-343Crossref PubMed Scopus (35) Google Scholar With their bipartite functionality to induce immune activation and tolerance,6Steinman R.M. Banchereau J. Taking dendritic cells into medicine.Nature. 2007; 449: 419-426Crossref PubMed Scopus (1685) Google Scholar DCs are well suited to set the balance between immune suppression and immune reactivity. We hypothesized that under the influence of the RCC tumor milieu, specific DC subtypes could develop, which may participate in regulatory networks responsible for silencing antitumor effector lymphocytes.7Mantovani A. Romero P. Palucka A.K. Marincola F.M. Tumour immunity: effector response to tumour and role of the microenvironment.Lancet. 2008; 371: 771-783Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar DCs have been extensively studied in lymphoid organs, yet outside the lymphoid environment their effector biology is still poorly understood.8Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1164) Google Scholar, 9Geissmann F. Gordon S. Hume D.A. Mowat A.M. Randolph G.J. Unravelling mononuclear phagocyte heterogeneity.Nat Rev Immunol. 2010; 10: 453-460Crossref PubMed Scopus (416) Google Scholar Once in a tissue, phenotypic and functional diversifications can occur, depending on organ- and compartment-specific microenvironments.10Gordon S. Taylor P.R. Monocyte and macrophage heterogeneity.Nat Rev Immunol. 2005; 5: 953-964Crossref PubMed Scopus (3822) Google Scholar, 11Segerer S. Heller F. Lindenmeyer M.T. Schmid H. Cohen C.D. Draganovici D. Mandelbaum J. Nelson P.J. Grone H.J. Grone E.F. Figel A.M. Nossner E. Schlondorff D. Compartment specific expression of dendritic cell markers in human glomerulonephritis.Kidney Int. 2008; 74: 37-46Crossref PubMed Scopus (116) Google Scholar Indeed, plasticity and functional polarity are hallmarks of the DC/macrophage lineage, leading to considerable discussion concerning the subtype-specific nomenclature.8Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1164) Google Scholar, 9Geissmann F. Gordon S. Hume D.A. Mowat A.M. Randolph G.J. Unravelling mononuclear phagocyte heterogeneity.Nat Rev Immunol. 2010; 10: 453-460Crossref PubMed Scopus (416) Google Scholar, 12Naik S.H. Demystifying the development of dendritic cell subtypes, a little.Immunol Cell Biol. 2008; 86: 439-452Crossref PubMed Scopus (129) Google Scholar, 13Heath W.R. Carbone F.R. Dendritic cell subsets in primary and secondary T cell responses at body surfaces.Nat Immunol. 2009; 10: 1237-1244Crossref PubMed Scopus (349) Google Scholar, 14Steinman R.M. Idoyaga J. Features of the dendritic cell lineage.Immunol Rev. 2010; 234: 5-17Crossref PubMed Scopus (169) Google Scholar Mouse models have been instrumental in deconstructing the diversity, yet comparable information for the human system is still sparse.8Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells.Annu Rev Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1164) Google Scholar, 9Geissmann F. Gordon S. Hume D.A. Mowat A.M. Randolph G.J. Unravelling mononuclear phagocyte heterogeneity.Nat Rev Immunol. 2010; 10: 453-460Crossref PubMed Scopus (416) Google Scholar, 13Heath W.R. Carbone F.R. Dendritic cell subsets in primary and secondary T cell responses at body surfaces.Nat Immunol. 2009; 10: 1237-1244Crossref PubMed Scopus (349) Google Scholar Among peripheral organs, the lung, skin, and kidney have wellestablished DC biology. In murine kidney, DCs are a prominent cell type largely restricted to the tubulointerstitial region.15Dong X. Swaminathan S. Bachman L.A. Croatt A.J. Nath K.A. Griffin M.D. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury.Kidney Int. 2007; 71: 619-628Crossref PubMed Scopus (276) Google Scholar, 16Kurts C. Heymann F. Lukacs-Kornek V. Boor P. Floege J. Role of T cells and dendritic cells in glomerular immunopathology.Semin Immunopathol. 2007; 29: 317-335Crossref PubMed Scopus (54) Google Scholar It has been proposed that the murine kidney DCs exert regulatory functions that help protect the tubulointerstitium from immune cell injury.16Kurts C. Heymann F. Lukacs-Kornek V. Boor P. Floege J. Role of T cells and dendritic cells in glomerular immunopathology.Semin Immunopathol. 2007; 29: 317-335Crossref PubMed Scopus (54) Google Scholar, 17Scholz J. Lukacs-Kornek V. Engel D.R. Specht S. Kiss E. Eitner F. Floege J. Groene H.J. Kurts C. Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis.J Am Soc Nephrol. 2008; 19: 527-537Crossref PubMed Scopus (102) Google Scholar Clear cell RCCs arise from the renal tubular epithelial cells. If DCs within the carcinoma experience an environmental polarization with acquisition of similar functional characteristics, they could contribute to the silencing of the tumor's immune infiltrate. Recent studies have attempted to link the presence of DCs to prognosis and response to therapy in human kidney disease11Segerer S. Heller F. Lindenmeyer M.T. Schmid H. Cohen C.D. Draganovici D. Mandelbaum J. Nelson P.J. Grone H.J. Grone E.F. Figel A.M. Nossner E. Schlondorff D. Compartment specific expression of dendritic cell markers in human glomerulonephritis.Kidney Int. 2008; 74: 37-46Crossref PubMed Scopus (116) Google Scholar, 18Woltman A.M. de Fijter J.W. Zuidwijk K. Vlug A.G. Bajema I.M. van der Kooij S.W. van Ham V. van Kooten C. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions.Kidney Int. 2007; 71: 1001-1008Crossref PubMed Scopus (111) Google Scholar and in RCC.5Frankenberger B. Noessner E. Schendel D.J. Immune suppression in renal cell carcinoma.Semin Cancer Biol. 2007; 17: 330-343Crossref PubMed Scopus (35) Google Scholar, 19Kobayashi M. Suzuki K. Yashi M. Yuzawa M. Takayashiki N. Morita T. Tumor infiltrating dendritic cells predict treatment response to immmunotherapy in patients with metastatic renal cell carcinoma.Anticancer Res. 2007; 27: 1137-1141PubMed Google Scholar, 20Gigante M. Blasi A. Loverre A. Mancini V. Battaglia M. Selvaggi F.P. Maiorano E. Napoli A. Castellano G. Storkus W.J. Gesualdo L. Ranieri E. Dysfunctional DC subsets in RCC patients: ex vivo correction to yield an effective anti-cancer vaccine.Mol Immunol. 2009; 46: 893-901Crossref PubMed Scopus (37) Google Scholar Here, we document that RCCs harbor unusually differentiated DCs, referred to as enriched-in-renal-carcinoma DCs (ercDCs), which use the crosstalk with lymphocytes to cause milieu alterations associated with tumor promotion and reduced TH1-polarized effector cell recruitment, promoting escape from the antitumor immune response. RCC tissues were clear cell RCCs from untreated patients (Table 1). Nontumor kidney cortices (NKCs) were from tumor-free areas of tumor-bearing kidneys. Tumor peripheral areas were selected macroscopically and covered the tumor “pseudocapsule” and the adjacent regions of nontumor and malignant tissue (see Supplemental Figure S1A at http://ajp.amjpathol.org). Tissues were snap frozen after nephrectomy and stored at −86°C. Peripheral blood mononuclear cells were from healthy individuals. Sample collection was performed after informed consent and approved by the ethics committee.Table 1Clinicopathologic Features of Patients with Clear Cell RCCFeaturesNo. of patientsRCC Tumor size⁎Tumor staging was determined according to UICC (2002/2003). pT115 pT25 pT322 pT41 Nodal status†Nodal status includes only regional lymph nodes. pN039 pN10 pN24 Distant metastasis pM034 pM19 Histopathologic grading G1 (good)2 G2 (moderate)28 G3 (poor)12 Gx (undetermined)1 Tumor staging I14 II3 III12 IV14 Age, median (range), years67 (34–87) Sex Male25 Female18 Total43NKC Age, median (range), years68 (38–83) Sex Male10 Female7 Total17 Tumor staging was determined according to UICC (2002/2003).† Nodal status includes only regional lymph nodes. Open table in a new tab Primary and secondary antibodies and their application are listed in Table 2.Table 2Antibodies and ApplicationsAntibodyLabelCloneSpecies/isotypeCompanyApplicationPrimary antibody BDCA-1L161MouseImmunotechIHC, IF BDCA-3AD5-14H12MouseMiltenyiIHC, IF CD3ϵpolyclonalRabbitDakoIHC CD3ϵUCHT1Mouse IgG1DakoIHC, IF, FC CD3ϵPBUCHT1Mouse IgG1DakoFC CD3ζ8D3Mouse IgG1BD BiosciencesIHC, IF, FC CD3ζFITCG3Mouse IgG2aSerotecFC CD8C8/144BMouse IgG1DakoIHC CD8PBRPA-T8Mouse IgG1BD BiosciencesFC CD14RMO52Mouse IgG2aImmunotechIHC, IF, FC CD14PBM5E2Mouse IgG2aBD BiosciencesFC CD15FITCHI98MouseBD BiosciencesFC CD16FITC3G8Mouse IgG1BD BiosciencesFC CD40FITC5C3Mouse IgG1BD BiosciencesFC CD45PE-Cy7HI30MouseBD BiosciencesFC CD56APCN901Mouse IgG1Beckman CoulterFC CD80FITCBB1Mouse IgMBD BiosciencesFC CD83HB15AMouse IgG2bImmunotechIHC CD86PE2331/FUN-1Mouse IgG1BD BiosciencesFC CD107aFITCH4A3Mouse IgG1BD BiosciencesFC CD107bFITCH4B4Mouse IgG1BD BiosciencesFC CD163Ber-MAC3Mouse IgG1DakoIHC, IF, FC CD163PEGHI/61Mouse IgG1BD BiosciencesFC CD209/DC-SIGNDCN46Mouse IgG2bBD BiosciencesIHC, IF, FC CD209/DC-SIGNAPCDCN46Mouse IgG2bBD BiosciencesFC CD274/B7-H1FITCMIH1Mouse IgG1BD BiosciencesFC CX3CR1PolyclonalRabbiteBioscienceFC CD208/DC-LAMP104.G4Mouse IgG1ImmunotechIHC FOXP3259DMouse IgG1BioLegendIHC, IF Granzyme BPEGB11Mouse IgG1SerotecFC HLA-ABC/MHC-IAPCG46_2.6Mouse IgG1BD BiosciencesFC HLA-DR/MHC-IIFITCL243Mouse IgG2aBD BiosciencesFC HLA-DR/MHC-IIPEG46-6Mouse IgG2aBD BiosciencesFC IFN-γPE-Cy74S.B3Mouse IgG1BD BiosciencesFC IL-2APCMQ1-17H12Rat IgG2aBD BiosciencesFC IsotypeFITCMOP-C21Mouse IgG1BD BiosciencesFC IsotypePEMOP-C21Mouse IgG1BD BiosciencesFC PerforinFITCδG9Mouse IgG2bBD BiosciencesFC TNF-αA700Mab11Mouse IgG1BD BiosciencesFCSecondary antibody Anti-APAPMouse IgG1DakoIHC (APAAP) Anti-mouseRabbitDakoIHC (APAAP) Anti-mouseHRPGoatDianovaIHC (doublestain) Anti-mouse IgG1A488GoatMolecular ProbesFC Anti-mouse IgG1A568GoatMolecular ProbesIF Anti-mouse IgG2aA568GoatMolecular ProbesIF Anti-mouse IgG2aA647GoatMolecular ProbesIF Anti-mouse IgG2bA488GoatMolecular ProbesIF Anti-rabbitA488GoatMolecular ProbesFC Anti-rabbitAPGoatDianovaIHC Anti-rabbitCy5GoatDianovaIFA, Alexa Fluor; AP, alkaline phosphatase; APC, allophycocyanin; Cy, cyanin; FC, flow cytometry; HRP, horseradish peroxidase; IF, immunofluorescence; PB, Pacific blue; PE, phycoerythrin. Open table in a new tab A, Alexa Fluor; AP, alkaline phosphatase; APC, allophycocyanin; Cy, cyanin; FC, flow cytometry; HRP, horseradish peroxidase; IF, immunofluorescence; PB, Pacific blue; PE, phycoerythrin. Cryosections (5-μm thick) were stained using the alkaline phosphatase antialkaline phosphatase (APAAP) method21Ebelt K. Babaryka G. Figel A.M. Pohla H. Buchner A. Stief C.G. Eisenmenger W. Kirchner T. Schendel D.J. Noessner E. Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma.Prostate. 2008; 68: 1-10Crossref PubMed Scopus (48) Google Scholar or dual-labeling immunohistochemistry (IHC) (see Supplemental Figure S1, B and C, at http://ajp.amjpathol.org). Cryosections were incubated with primary antibodies [rabbit-anti-human CD3 and mouse-anti-human CD208/DC-Lamp, diluted in Tris-buffered saline with human serum (HS)] followed by secondary antibodies alkaline phosphatase-conjugated anti-rabbit immunoglobulin (Immunoresearch, West Grove, PA) and peroxidase-conjugated anti-mouse immunoglobulin (Immunoresearch). Detection was done with substrate Fast Blue followed by substrate aminoethylcarbazol (both from Sigma-Aldrich, Taufkirchen, Germany). Stained tissue sections were mounted using Immunomount (Vector Laboratories, Burlingame, CA). NK cell quantification in tissue was not possible by single-marker histologic analysis for the following reasons. The commonly used NK cell marker CD56 did not work reproducibly in cryosections. Moreover, CD56 is also expressed by a subset of cytotoxic T lymphocytes (CTLs)22Pittet M.J. Speiser D.E. Valmori D. Cerottini J.C. Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression.J Immunol. 2000; 164: 1148-1152PubMed Google Scholar and thus gives cell counts not necessarily related to the NK cell number in a tissue.23Halama N. Braun M. Kahlert C. Spille A. Quack C. Rahbari N. Koch M. Weitz J. Kloor M. Zoernig I. Schirmacher P. Brand K. Grabe N. Falk C.S. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines.Clin Cancer Res. 2011; 17: 678-689Crossref PubMed Scopus (213) Google Scholar NKp46 is a marker that is exclusively expressed by NK cells; however, it is subjected to regulation by the tumor milieu.24Gazit R. Mandelboim O. Natural killer cells at the tumors microenvironment.in: Yefenof E. Innate and adaptive immunity in the tumor microenvironment. Springer, New York2008: 171-193Crossref Google Scholar In particular, we observed down-regulation on a large proportion of NK cells of tumor-infiltrating lymphocytes (TILs) from RCC tissues using flow cytometry (P.P., unpublished observation). Therefore, the NK cell content in a tissue was determined as the percentage of NK cells (defined as CD3−CD56+) within TILs using flow cytometry. Cryosections 5-μm thick were fixed in ice-cold 100% acetone and blocked with 2% bovine serum albumin (BSA) in PBS before incubation with primary antibody combinations, followed by corresponding combinations of secondary isotype- or species-specific fluorescent-labeled antibodies. Secondary reagents showed no cross-reactivity. All antibodies were diluted in 12.5% HS (Cambrex, East Rutherford, NJ) in PBS and incubated at room temperature. The following antibody combinations were used: primary mouse-anti-human antibodies CD209/DC-SIGN, CD14, and CD163 followed by secondary antibodies anti-IgG2b-A488, anti-IgG2a-A568, and anti-IgG1-A647; primary mouse-anti-human antibodies CD209/DC-SIGN, CD14, and polyclonal rabbit-anti-CD3ε followed by secondary antibodies anti-IgG2b-A488, anti-IgG2a-A568, and anti-rabbit-Cy5; primary mouse-anti-human antibodies CD209/DC-SIGN, CD163, and polyclonal rabbit-anti-CD3ε followed by secondary antibodies anti-IgG2b-A488, anti-IgG1-A568, and anti-rabbit-Cy5; primary mouse-anti-human antibodies CD209/DC-SIGN, CD14, and FOXP3 followed by secondary antibodies anti-IgG2b-A488, anti-IgG2a-A647, and anti-IgG1-A568; primary mouse-anti-human antibodies CD209/DC-SIGN and CD3ζ, and rabbit-anti-CD3ε followed by secondary antibodies anti-IgG2b-A488, anti-IgG1-A568, and anti-rabbit-Cy5. Detailed antibody information is in Table 2. After fixation [4% paraformaldehyde (PFA)] and nuclear staining with DAPI (Sigma-Aldrich), slides were mounted with Vectashield (Vector Laboratories). Fluorescence images were captured with a laser scanning microscope TCS SP2 (Leica Microsystems, Wetzlar, Germany) using HCX PL APO 63 × 1.40 oil immersion objective lens, pinhole 1.0 Airy units, 512 × 512 pixel image format, and four-frame averaging at a magnification of ×630. Sequential recording was applied to avoid fluorescence spillover, and Z-stacks were scanned to detect cells and intercellular contacts across different planes of the visual field. Image editing of contrast and brightness was applied to the whole image using Leica LCS Lite software. CD209, CD14, and/or CD163 multiparameter-stained tissue sections were used. CD209+ cells were identified in three different areas of RCC-inflicted kidneys: NKCs (n = 8) and two different tumor regions, the tumor center (n = 11) and the tumor periphery (n = 6). Tissues representing the three tissue areas were selected macroscopically. NKC tissues were derived from regions with the longest possible distance away from any tumor region. Histologic sections were microscopically free of malignant cells. Histologic sections of the tumor periphery were cross-sectional cuts that microscopically encompassed nontumor kidney, the “pseudocapsule” that surrounds the tumor, separating it from the nontumor kidney area, and the tumor region (see Supplemental Figure S1A at http://ajp.amjpathol.org). Myeloid cells located in the tumor parenchyma next to the capsule (ie, the tumor periphery) were evaluated. Tumor center tissue regions were macroscopically selected to be clearly away from the “pseudocapsule.” The histologic sections showed no areas of nontumor kidney or the “pseudocapsule.” Of each tissue area, at least 10 nonoverlapping fields (×630 magnification) containing CD209+ cells were evaluated. The frequency of CD209+ cells with co-expression of CD14 and/or CD163 was quantified by assigning CD14 and CD163 expression to each CD209+ cell. Intercellular contacts between CD209+ cells and CD3+ or FOXP3+ cells were determined using multiparameter immunofluorescence-stained RCC or NKC sections. At least 10 nonoverlapping fields (×630) containing CD209+ cells were evaluated. The frequency of contacts between CD209+CD14+ or CD209+CD163+ cells and CD3+ lymphocytes was assessed by selecting CD209+ cells and assigning co-expression of CD14 or CD163 and contacts with CD3+ lymphocytes. Intercellular contacts between FOXP3+ and CD209+CD14+ cells were quantified by selecting FOXP3+ fields. CD3ζ, CD3ε, and CD209 multiparameter immunofluorescence-stained RCC sections were evaluated. Images containing CD209+ and CD3+ cells were captured at ×630 magnification. Fluorescence intensity of CD3ζ and CD3ε of T cells in close contact to CD209+ cells and those away from CD209+ cells was compared. Cell-conditioned media were generated from cell lines25Engels B. Noessner E. Frankenberger B. Blankenstein T. Schendel D.J. Uckert W. Redirecting human T lymphocytes toward renal cell carcinoma specificity by retroviral transfer of T cell receptor genes.Hum Gene Ther. 2005; 16: 799-810Crossref PubMed Scopus (44) Google Scholar, 26Djafarzadeh R. Noessner E. Engelmann H. Schendel D.J. Notohamiprodjo M. von Luettichau I. Nelson P.J. GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing.Oncogene. 2006; 25: 1496-1508Crossref PubMed Scopus (23) Google Scholar (Table 3) by culturing 2 × 106 cells in 10 mL of serum-free AIM-V (Gibco/Invitrogen, Carlsbad, CA) for 10 days. Supernatants were centrifuged to remove cells. Cytotoxic T-effector cell clones CTL-JB4 (HLA-A2 alloreactive) and CTL-A42 (HLA-A2 restricted, MELAN/MART-1 specific) (Table 3) were cultured as described27Milani V. Frankenberger B. Heinz O. Brandl A. Ruhland S. Issels R.D. Noessner E. Melanoma-associated antigen tyrosinase but not Melan-A/MART-1 expression and presentation dissociate during the heat shock response.Int Immunol. 2005; 17: 257-268Crossref PubMed Scopus (25) Google Scholar and used at a resting state, generally between days 8 and 10 after the last restimulation, when they no longer secreted cytokines spontaneously. Both are TH1-polarized effector cells as evidenced by high expression of the chemokine receptor CXCR3 and CCR5.Table 3Cell LinesCell lineTissue/cell originSource or referenceRCC-26Clear cell renal cell carcinoma of patient 2622Pittet M.J. Speiser D.E. Valmori D. Cerottini J.C. Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression.J Immunol. 2000; 164: 1148-1152PubMed Google ScholarRCC-53Clear cell renal cell carcinoma of patient 5323Halama N. Braun M. Kahlert C. Spille A. Quack C. Rahbari N. Koch M. Weitz J. Kloor M. Zoernig I. Schirmacher P. Brand K. Grabe N. Falk C.S. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines.Clin Cancer Res. 2011; 17: 678-689Crossref PubMed Scopus (213) Google ScholarA-498Clear cell renal cell carcinomaATCC, HTB-44CCA23Clear cell renal cell carcinoma27Milani V. Frankenberger B. Heinz O. Brandl A. Ruhland S. Issels R.D. Noessner E. Melanoma-associated antigen tyrosinase but not Melan-A/MART-1 expression and presentation dissociate during the heat shock response.Int Immunol. 2005; 17: 257-268Crossref PubMed Scopus (25) Google ScholarHK-2Proximal tubular epithelial cellsATCC, CRL-2190NKC-26Normal kidney cells22Pittet M.J. Speiser D.E. Valmori D. Cerottini J.C. Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression.J Immunol. 2000; 164: 1148-1152PubMed Google ScholarJurkatT-cell leukemia cellsATCC, TIB-153Colo-357Pancreatic cancerDepartment of Clinical Pharmacology, LMUDU-145Prostate cancerATCC, HTB-81Mel93.04A12Melanoma (HLA-A2+ tyrosinase+)P. Schier, LeidenLCL-26B-lymphoblastoid cells of patient 2622Pittet M.J. Speiser D.E. Valmori D. Cerottini J.C. Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression.J Immunol. 2000; 164: 1148-1152PubMed Google ScholarCTL-JB4Cytotoxic T cells, HLA-A2 allospecific24Gazit R. Mandelboim O. Natural killer cells at the tumors microenvironment.in: Yefenof E. Innate and adaptive immunity in the tumor microenvironment. Springer, New York2008: 171-193Crossref Google ScholarCTL-A42Cytotoxic T cells, HLA-A2-restricted Melan-A/MART-1 peptide (AAGIGILTV) specific24Gazit R. Mandelboim O. Natural killer cells at the tumors microenvironment.in: Yefenof E. Innate and adaptive immunity in the tumor microenvironment. Springer, New York2008: 171-193Crossref Google Scholar Open table in a new tab The TILs were isolated from fresh tissues immediately after surgical resection. Briefly, tissues were mechanically minced into small pieces and washed with HBSS buffer to remove contaminating blood lymphocytes. Intratumoral leukocytes were recovered from the tissue after two enzymatic digestions using collagenase IA (0.5 mg/mL) and DNase I type IV (0.19 mg/mL) (all from Sigma-Aldrich) with an intermittent step of 5 mmol/L EDTA in HBSS (without Ca2+ and Mg2+). All incubations were performed for 30 minutes at room temperature. Monocytes were isolated from peripheral blood mononuclear cells using CD14+ microbeads (Miltenyi) and cultivated serum free (5 × 106/4 mL of AIM-V) with IL-4 (400 U/mL; CellGenix, Freiburg, Germany) and granulocyte-macrophage colony-stimulating factor (GM-CSF/Leukine; 800 U/mL; Genzyme, Cambridge, MA) to generate CD209 single-positive conventional DCs (cDCs). For tissue-conditioned cells, monocytes were cultivated with 20% cell-conditioned media or with CXCL8/IL-8 (7 ng/mL; PeproTech, Rocky Hill, NJ), IL-6 (1.9 ng/mL), and vascular endothelial growth factor (VEGF) (23.4 ng/mL) (both R&D Systems, Minneapolis, MN) or in combinations. The concentrations reflected those of RCC-26–conditioned medium. Functional analyses were performed with monocytes generated with RCC-26–conditioned medium. Myeloid cells within one experiment were derived from the same donor. Multicellular spheroids were generated as previously described.28Carlsson J. Yuhas J.M. Liquid-overlay culture of cellular spheroids.Recent Results Cancer Res. 1984; 95: 1-23Crossref PubMed Scopus (165) Google Scholar In brief, 105 suspended cells from exponentially growing RCC-53 monolayers were cultured on 1% solid seaplaque agarose (Biozym, Wien, Austria) in 24-well plates. After 4 days, the tight aggregates were transferred to 20 μL of AIM-V containing 105 monocytes and cultured as hanging drops on the lid of a petri dish. After 24 hours, noninfiltrated monocytes were removed and the spheroids cultured for 3 more days. Thereafter, spheroids were dispersed in 5 mmol/L EDTA (mechanic disruption) and the single-cell suspension was analyzed by flow cytometry using LSRII (gated on CD45+ cells) (BD Pharmingen, San Diego, CA) and FlowJo (TreeStar, Ashlan, OR). For macropinocytosis, cells (3 × 105 cells/600 μL) were incubated with fluorescein isothiocyanate (FITC)–labeled BSA (1 mg/mL; Sigma-Aldrich) for 1 hour at 37°C or 4°C (control) and analyzed by flow cytometry. Endocytosis involved FITC-labeled dextran (500 kDa; Sigma-Aldrich). For phagocytosis, the Vybrant phagocytosis assay (Molecular Probes/Invitrogen) was used. Antigen cross-presentation was performed as previously described.29Bendz H. Ruhland S.C. Pandya M.J. Hainzl O. Riegelsberger S. Brauchle C. Mayer M.P. Buchner J. Issels R.D. Noessner E. Human heat shock protein 70 enhances tumor antigen presentation through complex formation and intracellular antigen delivery without innate immune signaling.J Biol Chem. 2007; 282: 31688-31702Crossref PubMed Scopus (109) Google Scholar The system involves the HLA-A2–restricted Melan-A/MART-1–specific CTL-A42 and the pep70-MART peptide, which is an extended 15mer peptide containing the HLA-A2–re" @default.
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• W2027554407 title "Human Renal Cell Carcinoma Induces a Dendritic Cell Subset That Uses T-Cell Crosstalk for Tumor-Permissive Milieu Alterations" @default.
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