Lack of interleukin‐2 (IL‐2) expression and selective expression of IL‐10 mRNA in human renal cell carcinoma

Nakagomi, Hiroshi; Pisa, Pavel; Pisa, Eva K.; Yamamoto, Yasuyoshi; Halapi, Eva; Backlin, Karin; Juhlin, Claes; Kiessling, Rolf

doi:10.1002/ijc.2910630311

Cited by 119 publications

(70 citation statements)

References 24 publications

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“…This is consistent with the undetectable or minimal cytolytic activities of purified and IL-2-expanded RCC TIL in other studies [26,[28][29][30]. IL-10 has potent inhibitory effects on cytotoxic T cell responses [31], and it is therefore possible that the production of IL-10 in the tumour microenvironment by CD4 þ TIL, as shown here and by others [12,32,33], may explain the poor cytolytic activity of CD3 þ CD8 þ TIL in RCC. The inadequate up-regulation of CD25 on CD3 þ CD8 þ TIL, but not CD4 þ TIL, following triggering by anti-CD3 may be equally relevant to their low cytolytic activity.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Phenotype, cytokine production and cytolytic capacity of fresh (uncultured) tumour-infiltrating T lymphocytes in human renal cell carcinoma

Hove¹,

Gool²,

Poppel³

et al. 1997

Clinical and Experimental Immunology

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SUMMARYWe investigated the phenotype and functional capacities of tumour-infiltrating lymphocytes (TIL), freshly isolated from primary renal cell carcinoma (RCC) specimens (n ¼ 20). Three-colour flow cytometry immunophenotyping revealed that RCC TIL consist mainly of CD3 þ T cells, with a clear predominance of CD4 ¹ CD8 þ over CD4 þ CD8 ¹ T cells, and a marked population of CD4 þ CD8 þ T cells. Natural killer (NK) cells were also strongly represented (> 25% in 15 of 20 tumour samples), while B cells constituted a minor TIL subset (< 5% in 18 of 20 tumour samples). More importantly, the T and NK cells within the tumour displayed a significantly higher expression of the early activation marker CD69 than their counterparts in adjacent normal renal tissue and in peripheral blood. Expression of CD54 and of HLA-DR was also elevated on CD3 þ TIL, and HLA-DR expression was further vigorously up-regulated following ex vivo stimulation with anti-CD3, all suggesting enhanced immune activity within the tumour microenvironment. CD3 þ CD4 þ TIL displayed a normal capacity to up-regulate CD25 expression and to secrete both Th1-type (IL-2, tumour necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-g)) and Th2-type (IL-4, IL-5 and IL-10) cytokines upon triggering with anti-CD3. Furthermore, cytokine production was susceptible to modulation by CD28 costimulation. CD3 þ CD8 þ TIL, on the other hand, consistently demonstrated a poor up-regulation of CD25 upon triggering with anti-CD3, and displayed poor ex vivo cytolytic activity in an anti-CD3-redirected 4-h cytotoxicity assay against murine P815 cells. Collectively, our findings indicate that the CD3 þ CD4 þ TIL in RCC have normal functional capacities, whereas the proportionally major CD3 þ CD8 þ TIL are functionally impaired. The relevance of these findings to the in vivo local immune response in RCC is discussed.

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Section: Discussionsupporting

confidence: 92%

“…Furthermore, the relevance of effector functions mediated by in vitro grown TIL lines to the in vivo situation remains to be established, and possible artefacts involved in long-term in vitro growth of TIL limit the interpretation of numerous functional studies [12].…”

Section: Introductionmentioning

confidence: 99%

Phenotype, cytokine production and cytolytic capacity of fresh (uncultured) tumour-infiltrating T lymphocytes in human renal cell carcinoma

Hove¹,

Gool²,

Poppel³

et al. 1997

Clinical and Experimental Immunology

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“…Our finding of high IL-10 mRNA levels in TIL is in accordance with results reported by Wang et al, who detected IL-10 mRNA in freshly-isolated lymphocyteenriched preparations from 4/5 RCC tumour specimens (Wang et al, 1995) and by Maeurer et al, who found that uncultured TIL from seven RCC patients expressed IL-10 and IL-4 mRNA (Maeurer et al, 1995). Other authors reported a high expression of IL-10 mRNA in biopsies of renal cell carcinomas (Filgueira et al, 1993;Nakagomi et al, 1995;Olive et al, 1997). A concomitant high expression of the Th2 cytokine IL-10 and the Th1 cytokine IFN-γ has been recently shown in isolated CD3 + TIL from RCC (Elsässer-Beile et al, 1999).…”

Section: Discussionsupporting

confidence: 87%

Enhanced expression of IFN-γ mRNA in CD4+ or CD8+ tumour-infiltrating lymphocytes compared to peripheral lymphocytes in patients with renal cell cancer

et al. 2000

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SummaryThe mRNA expression of the cytokines IFN-γ, IL-10 and TNF-α and the proapoptotic factor Fas ligand (FasL) was compared in freshly isolated CD4 + and CD8 + tumour-infiltrating lymphocytes (TIL) and simultaneously obtained autologous CD4 + and CD8 + peripheral blood lymphocytes (PBL) from 20 patients with renal cell carcinomas (RCC). TIL were isolated from mechanically disaggregated tumour material and PBL from peripheral blood by gradient centrifugation. The cells of the interphase were depleted from tumour cells with antihuman epithelial antigen magnetic beads and then positive selection was performed with anti-CD4 or anti-CD8 magnetic beads. In these pure lymphocyte preparations the constitutive expression of cytokine and FasL mRNAs was determined by using a PCR-assisted mRNA amplification assay. In the CD4 + TIL from the 20 patients with RCC, levels of mRNAs encoding for IFN-γ (P ≤ 0.001), IL-10 (P ≤ 0.05), and FasL (P ≤ 0.001) were significantly higher than in the autologous CD4 + PBL. Comparison of CD8 + TIL and CD8 + PBL revealed a significant higher expression of IFN-γ (P ≤ 0.001), IL-10 (P ≤ 0.01) and FasL mRNAs (P ≤ 0.001) in the former. However, TNF-α mRNA levels were significantly lower in the CD8 + TIL than in the CD8 + PBL (P ≤ 0.05). These data reflect a general in vivo activation of RCC infiltrating lymphocytes in the tumour surrounding.

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“…The detection of IL-lO mRNA in more than half of the breast tumours and the failure to detect IL-2 mRNA is consistent with previous work shown by others that IL-10 may have an inhibitory role on IL-2 production and T-cell activation. Indeed, lack of detection of IL-2 expression with selective expression of IL-10 in TILs derived from human renal cell carcinoma (RCC) was recently reported in human renal cell carcinomas, further implicating a role for IL-10 in the immunosuppression of TILs (Nakagomi et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

High incidence of interleukin 10 mRNA but not interleukin 2 mRNA detected in human breast tumours

Venetsanakos

Beckman²,

Bradley³

et al. 1997

Br J Cancer

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Summary Despite the presence of a lymphocytic infiltrate in solid cancers, the failure for tumour growth to be contained suggests an inadequate immune response to the tumour. Poor cytotoxicity exerted by tumour-infiltrating lymphocytes (TILs) against tumour cells in vitro, combined with continued tumour growth in vivo, suggests deficiencies in TIL function or numbers. Various theories have been postulated to explain how tumour cells may escape immunosurveillance and control. One of the many hypotheses is the failure of production of cytokines, which are necessary for T cells to mediate their function. Thus, the expression of cytokine mRNA in human breast tumour sections was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) with cytokine-specific primers. A relatively consistent finding was detection of interleukin (IL) 10 mRNA among the tumours. No IL-2 and little IL-4 mRNA was detected in the tumours. IL-6 and IL-10 mRNA was detected in only one and two of the normal breast tissues respectively. IL-2, IL-4 and tumour necrosis factor (TNF)-a mRNA was not detected in any of the normal breast tissues. The reduced function of TILs may be related to IL-10, which has known inhibitory effects on T-cell activation.

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Lack of interleukin‐2 (IL‐2) expression and selective expression of IL‐10 mRNA in human renal cell carcinoma

Cited by 119 publications

References 24 publications

Phenotype, cytokine production and cytolytic capacity of fresh (uncultured) tumour-infiltrating T lymphocytes in human renal cell carcinoma

Phenotype, cytokine production and cytolytic capacity of fresh (uncultured) tumour-infiltrating T lymphocytes in human renal cell carcinoma

Enhanced expression of IFN-γ mRNA in CD4+ or CD8+ tumour-infiltrating lymphocytes compared to peripheral lymphocytes in patients with renal cell cancer

High incidence of interleukin 10 mRNA but not interleukin 2 mRNA detected in human breast tumours

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