T cell-mediated elimination of cancer cells by blocking CEACAM6–CEACAM1 interaction

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation.

Overexpression of CEACAM6 activates Src-FAK signaling and inhibits anoikis, through homophilic interactions in lung adenocarcinomas

“…If the antibodies or chemicals, which block the interaction of CEACAM6 demonstrate, inhibition of the FAK-Src pathway and restoration of anoikis, it would be additional evidence supporting their clinical development. Along with the recent report by Pinkert et al., their humanized monoclonal antibody selectively blocking CEACAM6 would be of great help in solving this problem [35] .…”

“…The researchers showed that when CEACAM6 was overexpressed or attached to cancer cells using beads, it inhibited the phosphorylation of zeta-chain-associated protein kinase 70 to suppress T-cell receptor-mediated T-cell responses. Furthermore, the Tinurilimab showed an increased tumor cell killing effect in the tumor-cell/T-cell co-culture system [ 34 , 35 ]. Our findings provide additional evidence that CEACAM6 is a possible target candidate for the treatment of lung cancer.…”

Comparison of CEA and CA19-9 as a predictive factor for recurrence after curative gastrectomy in gastric cancer

“…CEACAM6 (CEA-related cell adhesion molecule 6) is a cell adhesion protein of the CEA family and expressed on normal epithelial tissue, and its overexpression is associated with development, invasion, and metastasis of cancer [ 9 ]. Blockade of CEACAM6 reactivated the antitumor response of T cells in a previous study using cell lines [ 10 ], thus CEACAM6 might have something to do with angiogenesis and immunosuppression which is important in the growth of cancer [ 11 ]. CA19-9 is often increased in patients with pancreatic ductal adenocarcinoma as well as other gastrointestinal cancer including gastric cancer, and expression CA19-9 is associated with hyperactivation of epidermal growth factor receptor [ 12 ].…”

Structural analysis of human CEACAM1 oligomerization

“…The formation of cell surface hCEACAM1 monomers allows for trans-homophilic or heterophilic interactions critical to the induction of biologic responses 1 , 2 , 7 , 10 . Heterophilic ligands include a variety of microbes and host cell proteins such as hCEACAM5, hCEACAM6, the T cell inhibitory and mucin domain containing protein 3 (TIM-3) and potentially programmed cell death protein 1 (PD-1) 9 – 21 . In each case where it has been biochemically or biophysically defined, homophilic and heterophilic ligation depends upon GFCC’ face interactions 9 – 21 .…”

“…Heterophilic ligands include a variety of microbes and host cell proteins such as hCEACAM5, hCEACAM6, the T cell inhibitory and mucin domain containing protein 3 (TIM-3) and potentially programmed cell death protein 1 (PD-1) 9 – 21 . In each case where it has been biochemically or biophysically defined, homophilic and heterophilic ligation depends upon GFCC’ face interactions 9 – 21 . Consistent with the importance of the GFCC’ face for ligand interactions, the GFCC’ face also governs various states involved in hCEACAM1 dimerization.…”