Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer

Sivori, Simona; Chiesa, Mariella Della; Carlomagno, Simona; Quatrini, Linda; Munari, Enrico; Vacca, Paola; Tumino, Nicola; Mariotti, Francesca Romana; Mingari, Maria Cristina; Pende, Daniela; Moretta, Alessandro

doi:10.3389/fimmu.2020.02156

Cited by 66 publications

(57 citation statements)

References 129 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NC410 may also have additional LAIR-1-independent mechanisms of action since we have previously shown that LAIR-2 Fc can efficiently inhibit complement activation via classical and lectin pathways ( Olde Nordkamp et al, 2014a ). Therefore, we cannot exclude that NC410 blocks other receptors or impacts other cells than T cells ( Sivori et al, 2020 ) or has additional functions besides outcompeting LAIR-1. These functions of NC410 will be examined as part of ongoing clinical trials, as well as with additional preclinical models.…”

Section: Discussionmentioning

confidence: 99%

Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction

Ramos

Tian²,

Ruiter

et al. 2021

eLife

View full text Add to dashboard Cite

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1 mediated immune suppression. Analysis of public human datasets show that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction

Ramos

Tian²,

Ruiter

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…Sialic acids, extracellular matrix/collagen or aminophospholipids was expressed on the surface of tumor respectively, which could be recognized by sialic acids, extracellular matrix/collagen or aminophospholipids expressed on the surface of NK cells. Thus, NK cell function was inhibited (48).…”

Section: Tumor-infiltrated Nk Cells Exhibit An Altered Phenotypementioning

confidence: 99%

The Adverse Impact of Tumor Microenvironment on NK-Cell

Wei

2021

Front. Immunol.

View full text Add to dashboard Cite

NK cells are considered an important component of innate immunity, which is the first line of defensing against tumors and viral infections in the absence of prior sensitization. NK cells express an array of germline-encoded receptors, which allow them to eliminate abnormal cells and were previously considered a homogenous population of innate lymphocytes, with limited phenotypic and functional diversity. Although their characteristics are related to their developmental origins, other factors, such as tumors and viral infections, can influence their phenotype. Here, we provide an overview of NK cells in the context of the tumor microenvironment, with a primary focus on their phenotypes, functions, and roles in tumor micro-environment. A comprehensive understanding of NK cells in the tumor microenvironment will provide a theoretical basis for the development of NK cell immunotherapy.

show abstract

“…Tyrosine phosphorylation of ITIMs allows the recruitment of protein tyrosine phosphatases SHP-1 and SHP-2, leading to the transmission of inhibitory signals that limit the strength of signals received from activating receptors [ 27 ]. Classical NK cell inhibitory receptors bind to MHC molecules called HLA in humans [ 28 ]. Through these interactions, inhibitory NK cell receptors are responsible for the “missing-self recognition”, a process whereby NK cells recognize foreign or dangerous autologous cells that might have escaped adaptive immunity through down-regulation of surface class I MHC (MHC-I) molecule expression [ 29 ].…”

Section: Inhibitory Receptors Binding To Mhc-i Moleculesmentioning

confidence: 99%

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

Buckle

Guillerey

2021

Cancers

View full text Add to dashboard Cite

The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention.

show abstract

Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer

Cited by 66 publications

References 129 publications

Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction

Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction

The Adverse Impact of Tumor Microenvironment on NK-Cell

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

Contact Info

Product

Resources

About