Candida albicans evades NK cell elimination via binding of Agglutinin-Like Sequence proteins to the checkpoint receptor TIGIT

Abstract

Candida albicans is the most common fungal pathogen and a prevalent cause of deadly bloodstream infections. Better understanding of the immune response against it, and the ways by which it evades immunity, are crucial for developing new therapeutics against it. Natural Killer (NK) cells are innate lymphocytes best known for their role against viruses and tumors. In recent years it became clear that NK cells also play an important role in anti-fungal immunity. Here we show that while NK cells recognize and eliminate C. albicans, the fungal cells inhibit NK cells by manipulating the immune checkpoint receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) in both humans and mice. We identify the responsible fungal ligands as members of the Als (Agglutinin-Like Sequences) protein family. Furthermore, we show that blocking this interaction using immunotherapy with a TIGIT-blocking antibody can re-establish anti-Candida immunity and serve as a potential therapeutic tool.

Studying TIGIT activity against tumors through the generation of knockout mice

“…Recently, our lab identified the Agglutinin-Like Sequences (ALS) protein family as a novel fungal ligand for TIGIT in both human and mice 10 . Candida albicans can also be found in tumors such as oral 31 , colon cancer 32 as well as other forms of cancer 33 .…”

“…Labeled cells were then washed twice with RPMI serum-free medium and re-suspended in 2 mL of RPMI with 10% serum and counted. Murine splenocytes were produced from freshly harvested spleens of WT and TIGIT KO mice as previously described 10 . Isolated mice splenocytes were either activated with IL-2, or not activated, and then incubated with the calcein AM-labeled target cells (10,000 cells/well were seeded in 96 U-shaped plates) in an effector to target (E: T) ratio of 5:1 for 3 h at 37°C.…”

“…The bacterial Fap2 protein, which is expressed by Fusobacterium nucleatum and mediates adhesion to various bacteria and tumors, was also found to interact with human TIGIT but not with mouse TIGIT 9 . Fungal ligands belonging to the Als (Agglutinin-Like Sequences) protein family were reported to bind both human and mouse TIGIT 10 . Collectively, the interaction between TIGIT and its various ligands inhibits immune cell activities.…”

Manipulating NK cellular therapy from cancer to invasive fungal infection: promises and challenges

“…Binding between the Candida cell wall adhesins Epa1, Epa6, and Epa7, and NKp46 receptor and its mouse orthologue NCR1, resulted in enhanced NK activation through degranulation marker CD107, resulting in reduced fungal burden ( 86 ). Most recently, the Candida adhesin Agglutinin-Like Sequences (ALS) was identified as a ligand for TIGIT, an inhibitory checkpoint inhibitor on NK cells ( 87 ). CD56, a classical NK cell marker, has also been shown to be a major pathogen recognition receptor which directly interacts with A. fumigatus .…”

Nanomaterial‐Boosted Tumor Immunotherapy Through Natural Killer Cells

“…[10] In addition to the direct induction of cytotoxicity, the interaction of NK cells with other immune cells such as dendritic cells (DCs), T cells, and macrophages is of great relevance in enhancing and modulating antitumor immune responses. [11] So far, the elimination of NK cell activity triggered by immune checkpoint proteins such as T cell immunoglobulin and ITIM domains (TIGIT), [12] programmed cell death protein 1/programmed cell death-Ligand 1 (PD-1/PD-L1), [13] and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) [14] has become the target of immune checkpoint inhibition therapy. The promising combination therapy results of tiragolumab (TIGIT monoclonal antibody) and tecentriq (PD-L1 monoclonal antibody) prompted the initiation of a Phase III clinical trial (NCT04294810) in selected patients with high PD-L1 expression.…”