Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer.
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.


CONCLUSIONS
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.
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, The Netherlands.
Alexander
A
Pedroza-Gonzalez
Cornelis
C
Verhoef
Jan N M
JN
Ijzermans
Maikel P
MP
Peppelenbosch
Jaap
J
Kwekkeboom
Joanne
J
Verheij
Harry L A
HL
Janssen
Dave
D
Sprengers
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000473:pathology; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000627:therapeutic use*
D053450:Glucocorticoid-Induced TNFR-Related Protein; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; C491405:TNFRSF18 protein, human; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors