Effects of TGF-β on the immune system: implications for cancer immunotherapy

Visser, KE de; Kast, W. Martin

doi:10.1038/sj.leu.2401477

Cited by 145 publications

(98 citation statements)

References 53 publications

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“…Tumor-derived TGF-␤ has been shown to down-regulate the generation of tumorspecific cytotoxic lymphocytes (41)(42)(43) and the secretion of immunoregulatory cytokines by T cells (42). TGF-␤ can be a strong costimulator that promotes a shift toward Th2 polarity in rat activated T cells (44).…”

Section: Discussionmentioning

confidence: 99%

Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Sheu

Lin

Lien

et al. 2001

The Journal of Immunology

182

115

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Cytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-γ in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-β plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-β Abs. IL-10 and TGF-β are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-β in cancer-mediated immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Sheu

Lin

Lien

et al. 2001

The Journal of Immunology

182

115

View full text Add to dashboard Cite

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“…4 Tumor cells themselves or tumor-infiltrating immunomodulatory cells sometimes produce immunosuppressive cytokines and mediators such as TGF-, 15 IL-10, 16 and PGE 2 . 17 Cancer cells also inactivate NK cells or T cells directly by expressed on their surface Fas ligand, 18 mucins ( DF3 /MUC1 ), 19 or RCAS1.…”

Section: Discussionmentioning

confidence: 99%

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

et al. 2001

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“…During tumorigenesis one of the target genes that is preferentially inactivated due to MSI is transforming growth factor ␤ receptor II (TGF␤RII) (Markowitz et al, 1995;Akiyama et al, 1996). Inactivation of TGF␤RII on cells down-regulates the suppressive function of TGF␤ on cell proliferation and in that way also results in disturbance of growth control (DeVisser and Kast, 1999). Most of the hereditary nonpolyposis colorectal tumors (HNPCC) exhibit MSI, whereas in sporadic colorectal cancers only 3% to 10% show this phenotype.…”

mentioning

confidence: 99%

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

Jonges

Nagelkerke²,

Ensink

et al. 2001

Laboratory Investigation

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SUMMARY:Several techniques to determine apoptotic frequencies in tumors have been described. In this study, we report that biochemical detection of enzymatic caspase-3 activity is a simple and quantitative technique to measure apoptosis in colorectal tumor cells. The relevance of the level of apoptosis in colorectal cancer for the clinical course remains unclear. Therefore, we studied the correlation between caspase-3 activity and prognosis of the disease in relation to different factors known to be involved in apoptosis induction. High caspase-3 activity significantly correlated with a higher risk of recurrence and was preferentially found in tumors of the right side of the colon. No correlation was detected between high caspase-3 activity and altered protein expression of p53, ␤-catenin, or proteins of mismatched repair genes. This indicates that high caspase-3 activity has no evident correlation with the genetic Wnt-signaling or the mismatch repair mutational pathways. The caspase-3 activity significantly correlated with CD57 ϩ tumor infiltrating cells. Therefore, high caspase-3 activity in right-sided tumors might be induced by a specific lymphocytic reaction. (Lab Invest 2001, 81:681-688).A poptosis is an essential biologic process. As well as having a role in controlling cell number during early development, apoptosis is important for the removal of infected or genetically altered cells (Duke et al, 1996). Defects in the apoptotic mechanism are often found in neoplastic growth (Duke et al 1996;Green and Martin, 1995;Tompson, 1995), which is also the case in colorectal cancer (Evertsson et al, 1999;Gryfe et al, 1997;Tsujitani et al, 1996). Development of colorectal cancer proceeds through a series of genetic alterations that result in the activation of oncogenes and loss of tumor suppressor genes (Gryfe et al 1997;Rafter and Glinghammar, 1998;Ilyas et al, 1999). Mutations in genes known to be involved in cell cycle regulation, such as APC, p53, ␤-catenin, deleted in colorectal cancer (DCC), and K-ras, have been reported in colorectal cancer (reviewed in Gryfe et al, 1997). Furthermore, mutated genes involved in DNA mismatch repair can contribute to tumor growth. Alterations in these mismatch repair genes will lead to a microsatellite instability phenotype (MSI) (reviewed in Lothe, 1997). During tumorigenesis one of the target genes that is preferentially inactivated due to MSI is transforming growth factor ␤ receptor II (TGF␤RII) (Markowitz et al, 1995;Akiyama et al, 1996). Inactivation of TGF␤RII on cells down-regulates the suppressive function of TGF␤ on cell proliferation and in that way also results in disturbance of growth control (DeVisser and Kast, 1999). Most of the hereditary nonpolyposis colorectal tumors (HNPCC) exhibit MSI, whereas in sporadic colorectal cancers only 3% to 10% show this phenotype. This low rate of MSI in sporadic colorectal cancers seems to be caused by somatic inactivation of hMLH1 (Lothe, 1997).As well as the occurrence of apoptosis in cells caused by intrinsic factors, apopto...

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Effects of TGF-β on the immune system: implications for cancer immunotherapy

Cited by 145 publications

References 53 publications

Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

Caspase-3 Activity as a Prognostic Factor in Colorectal Carcinoma

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