Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

Louche, Calvin D. De; Roghanian, Ali

doi:10.1172/jci.insight.151553

Cited by 17 publications

(22 citation statements)

References 138 publications

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“…However, when hFcgRIIB is assessed in relation to other ITIM-containing immunoreceptors, it seems unlikely to deliver its regulatory function through ITIM signaling alone. hFcgRIIB possesses a single ITIM, whereas most inhibitory receptors contain two or more, with inhibitory leukocyte Ig-like receptors (LILR) ranging from two to four ITIMs (De Louche and Roghanian, 2022;van der Touw et al, 2017), SIRPa three ITIMs (Zen et al, 2013), and LAIR1 two ITIMs (Kang et al, 2015). Furthermore, there are usually multiple inhibitory receptors capable of regulating multiple activating receptors, such as within the KIR receptor system (Rajalingam, 2012).…”

Section: Discussionmentioning

confidence: 99%

FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

Simpson¹,

Roghanian²,

Oldham³

et al. 2022

Cell Reports

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Section: Discussionmentioning

confidence: 99%

FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

Simpson¹,

Roghanian²,

Oldham³

et al. 2022

Cell Reports

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“…The leukocyte Ig-like receptors, which includes LIR1, have been assigned roles in regulating innate and adaptive immunity. 27 The N-terminal Ig-motifs (D1 and D2) bind HLA-I/β2M class 24 and inhibitory signaling is mediated by ITIM tyrosine phosphorylation that recruits Src homology region 2 domain-containing phosphatase-1 (SHP-1) tyrosine phosphatase. 28 Our mechanistic analysis strongly suggests that the LIR1 iCAR operates by a similar mechanism since LIR1 ITIMs and A2 binding were found to be essential for protection.…”

Section: Discussionmentioning

confidence: 99%

HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity

Bassan,

Weinberger,

et al. 2023

J Immunother Cancer

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BackgroundOne of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 (“A2”) that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH).MethodsA CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2−HER2+lung cancer cell lines but spare A2+HER2+lung cancer cell-lines with high specificity. The extensive analysis of lead candidates included T-cell activation and killing, assays of reversibility and durability in sequential challenges, target cell specificity in mixed 3D spheroids and 2D cultures, and the characterization of CAR expression level and cell-trafficking.ResultsA leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the ‘on’ and ‘off’ cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2+cells in admix culture through aCAR dependent and independent mechanisms. LIR1 NOT gate CAR-T cells conferred protection against H1703-A2+tumors and high efficacy against H1703-A2−tumors in-vivo. We observed that the iCAR is inactive in A2+donors due to cis-binding, but Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout of HLA-A fully restored iCAR activity.ConclusionsWe have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.

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“…In addition, LILRB1 and LILRB2 are expressed by other immune cell populations. For example, LILRB1 is expressed by T cells and a subpopulation of NK cells ( 32 ). Therefore, manipulation of LILRB1 may also promote cytotoxic functions by lymphocytes ( 71 , 72 ).…”

Section: Discussionmentioning

confidence: 99%

“…Regarding that NK cells may express SIRPα in certain situations even co-blockade of LILRB1 and CD47 may be effective in enhancing NK cell-mediated ADCC ( 73 ). In neutrophils, conflicting results on the expression of LILRB1 were published, but LILRB2 is displayed ( 32 , 74 ). Albeit LILRB2-IgGσ lacked efficacy in enhancing ADCP by macrophages, it may be worth testing this antibody with neutrophils, in which blockade of the CD47-SIRPα axis was shown to enhance ADCC and trogoptosis ( 75 ).…”

Section: Discussionmentioning

confidence: 99%

“…Leukocyte immunoglobulin-like receptor (LILR) B 1 may represent another target for immune checkpoint blockade in monocytes and macrophages ( 10 , 31 ). LILRB1 and other members of the inhibitory subfamily B of LILR share structural similarities with human killer cell immunoglobulin-like receptors (KIR) and are characterized by cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) ( 32 ). In addition to several pathogen-derived ligands, LILRB1 binds classical human leukocyte antigen (HLA) class I as well as non-classical HLA-G and HLA-F molecules by interaction with the α3 domain and β2-microglobulin ( 33 – 35 ).…”

Section: Introductionmentioning

confidence: 99%

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Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages

Zeller¹,

Lutz²,

Münnich³

et al. 2022

Front. Immunol.

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Antibody-dependent cellular phagocytosis (ADCP) by macrophages, an important effector function of tumor targeting antibodies, is hampered by ‘Don´t Eat Me!’ signals such as CD47 expressed by cancer cells. Yet, human leukocyte antigen (HLA) class I expression may also impair ADCP by engaging leukocyte immunoglobulin-like receptor subfamily B (LILRB) member 1 (LILRB1) or LILRB2. Analysis of different lymphoma cell lines revealed that the ratio of CD20 to HLA class I cell surface molecules determined the sensitivity to ADCP by the combination of rituximab and an Fc-silent variant of the CD47 antibody magrolimab (CD47-IgGσ). To boost ADCP, Fc-silent antibodies against LILRB1 and LILRB2 were generated (LILRB1-IgGσ and LILRB2-IgGσ, respectively). While LILRB2-IgGσ was not effective, LILRB1-IgGσ significantly enhanced ADCP of lymphoma cell lines when combined with both rituximab and CD47-IgGσ. LILRB1-IgGσ promoted serial engulfment of lymphoma cells and potentiated ADCP by non-polarized M0 as well as polarized M1 and M2 macrophages, but required CD47 co-blockade and the presence of the CD20 antibody. Importantly, complementing rituximab and CD47-IgGσ, LILRB1-IgGσ increased ADCP of chronic lymphocytic leukemia (CLL) or lymphoma cells isolated from patients. Thus, dual checkpoint blockade of CD47 and LILRB1 may be promising to improve antibody therapy of CLL and lymphomas through enhancing ADCP by macrophages.

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Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

Cited by 17 publications

References 138 publications

FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity

Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages

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