A multimeric carcinoembryonic antigen signal inhibits the activation of human T cells by a SHP-independent mechanism: a potential mechanism for tumor-mediated suppression of T-cell immunity.
Carcinoembryonic antigen (CEA) is a well-known tumor antigen that is found in the serum of patients with various cancers and is correlated with an increased risk of cancer recurrence and metastasis. To understand the tumor environment and to develop antitumor therapies, CEA has been studied as an antigen to activate/tolerate specific T cells. In this study, we show that CEA can function as a coinhibitory molecule and can inhibit the activation of human peripheral blood mononucleated cell-derived T cells. The addition of CEA-overexpressing tumor cells or immobilized CEA dampened both cell proliferation and the expression of IL-2 and CD69 expression in T cells after TCR stimulation. The phosphorylation of ERK and translocation of NFAT were hampered in these cells, whereas the phosphorylation of proximal TCR signaling molecules such as ZAP70 and phospholipase Cγ was not affected by immobilized CEA. To determine the relevance of carcinoembryonic antigen-related cell adhesion molecule-1 and Src homology region 2 domain-containing phosphatase (SHP) molecules to CEA-mediated suppression, we tested the effect of the SHP inhibitor, NSC-87877, on CEA-mediated suppression of T cells; however, it did not reverse the effect of CEA. Collectively, these results indicate that CEA can function as a modulator of T-cell responses suggesting a novel mechanism of tumor evasion.
Laboratory of Immunology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Kyoo-A
KA
Lee
Eun-Ah
EA
Bae
You Chan
YC
Song
Eun-Kyung
EK
Kim
Yoon-Sook
YS
Lee
Tai-Gyu
TG
Kim
Chang-Yuil
CY
Kang
D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism*
D002272:Carcinoembryonic Antigen; C512715:NSC-87877; D011804:Quinolines; D011948:Receptors, Antigen, T-Cell; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
CEA; TCR signaling; adhesion molecule; coinhibitory signal; tumor-associated antigen