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

Abstract

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 Cc 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.

Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

“…To make human aGC-cultured supernatant, PBMCs were prepared by density gradient centrifugation using Ficoll-Histopaque-1077 Hybri-Max (Sigma-Aldrich) as described previously (34). To enrich for iNKT cells, PBMCs were cultured with aGC for 7 days and then cultured for an additional 7-10 days in the presence of recombinant human IL2 (200 U/mL).…”