CEACAM1 regulates TIM–3–mediated tolerance and exhaustion

By Yu‐Hwa Huang, Chen Zhu, Y. Kondo, A. Anderson, A. Gandhi, Andrew F. Russell, S. Dougan, B. Petersen, E. Melum, Thomas Pertel and 14 more. Nature, 2014

650 citations recorded by the source corpus.

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/6f9c92fac6667a02f92ca26acb59577ef26eac59

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In Immunology

1. D. Pardoll
2. S. Topalian
3. Charles G. Drake
4. G. Dranoff
5. G. Freeman
6. V. Kuchroo
7. A. Anderson
8. F. Hodi

In Oncology

1. D. Pardoll
2. G. Dranoff
3. S. Topalian
4. Charles G. Drake
5. F. Hodi
6. G. Freeman
7. J. Engelman
8. V. Kuchroo

Citations in the corpus

• Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints (2016, background): “CEACAM1 and phosphatidylserine have also been proposed as ligands for TIM-3 (refs 22,23).”
• Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 (2019, background): “Huang and his colleague elucidated that TIM-3 and Ceacam-1 can form a heterodimer in both cis and trans which acts as a negative regulator of T cell responses [88].”
• Immune checkpoint blockade: a common denominator approach to cancer therapy (2015, background): “Recent studies showed that TIM-3 is co-expressed with and binds to CECAM1 and that this interaction is important in TIM-30s regulatory function (Huang et al., 2015).”
• Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation (2016, background): “Lag-3 structurally resembles the CD4 co-receptor and, indeed, binds to MHC class II with a higher affinity than CD4 (Figure 1A; Huard et al., 1995).”