UNLABELLED: The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25- T cells. CONCLUSION: Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease.
UNLABELLED: The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25- T cells. CONCLUSION: Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease.
Authors: P Y Hernanda; K Chen; A M Das; K Sideras; W Wang; J Li; W Cao; S J A Bots; L L Kodach; R A de Man; J N M Ijzermans; H L A Janssen; A P Stubbs; D Sprengers; M J Bruno; H J Metselaar; T L M ten Hagen; J Kwekkeboom; M P Peppelenbosch; Q Pan Journal: Oncogene Date: 2014-12-22 Impact factor: 9.867
Authors: Alexander Pedroza-Gonzalez; Guoying Zhou; Ernesto Vargas-Mendez; Patrick Pc Boor; Shanta Mancham; Cornelis Verhoef; Wojciech G Polak; Dirk Grünhagen; Qiuwei Pan; Harry LA Janssen; Gina S Garcia-Romo; Katharina Biermann; Eric Ttl Tjwa; Jan Nm IJzermans; Jaap Kwekkeboom; Dave Sprengers Journal: Oncoimmunology Date: 2015-03-19 Impact factor: 8.110
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