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1.
PLoS One ; 19(6): e0304985, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38843278

RESUMEN

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.


Asunto(s)
Antígenos de Diferenciación , Antígeno CD47 , Inmunoconjugados , Receptores Inmunológicos , Antígeno CD47/antagonistas & inhibidores , Antígeno CD47/inmunología , Animales , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Humanos , Ratones , Inmunoconjugados/farmacología , Antígenos de Diferenciación/inmunología , Línea Celular Tumoral , Femenino , Trastuzumab/farmacología , Inhibidores de Topoisomerasa I/farmacología , Inmunoterapia/métodos , Ratones Endogámicos BALB C
2.
Front Immunol ; 15: 1362152, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38835768

RESUMEN

Introduction: The effector function of T cells is regulated via immune checkpoints, activating or inhibiting the immune response. The BTLA-HVEM complex, the inhibitory immune checkpoint, may act as one of the tumor immune escape mechanisms. Therefore, interfering with the binding of these proteins can prove beneficial in cancer treatment. Our study focused on peptides interacting with HVEM at the same place as BTLA, thus disrupting the BTLA-HVEM interaction. These peptides' structure and amino acid sequences are based on the gD protein, the ligand of HVEM. Here, we investigated their immunomodulatory potential in melanoma patients. Methods: Flow cytometry analyses of activation, proliferation, and apoptosis of T cells from patients were performed. Additionally, we evaluated changes within the T cell memory compartment. Results: The most promising compound - Pep(2), increased the percentages of activated T cells and promoted their proliferation. Additionally, this peptide affected the proliferation rate and apoptosis of melanoma cell line in co-culture with T cells. Discussion: We conclude that the examined peptide may act as a booster for the immune system. Moreover, the adjuvant and activating properties of the gD-derived peptide could be used in a combinatory therapy with currently used ICI-based treatment. Our studies also demonstrate that even slight differences in the amino acid sequence of peptides and any changes in the position of the disulfide bond can strongly affect the immunomodulatory properties of compounds.


Asunto(s)
Activación de Linfocitos , Melanoma , Receptores Inmunológicos , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Linfocitos T , Humanos , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Activación de Linfocitos/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Proliferación Celular/efectos de los fármacos , Anciano , Línea Celular Tumoral , Adulto , Apoptosis/efectos de los fármacos , Péptidos/farmacología , Péptidos/inmunología , Gangliósidos/inmunología
3.
J Clin Invest ; 134(11)2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38828721

RESUMEN

The adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and T cell coengineering to express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel of binding-enhanced A2/NY-TCRs including A97L, which augmented the in vitro function of gene-modified T cells as compared with WT. Here, we demonstrated higher persistence and improved tumor control by A97L-T cells. In order to harness macrophages in tumors, we further coengineered A97L-T cells to secrete a high-affinity signal regulatory protein α (SiRPα) decoy (CV1) that blocks CD47. While CV1-Fc-coengineered A97L-T cells mediated significantly better control of tumor outgrowth and survival in Winn assays, in subcutaneous xenograft models the T cells, coated by CV1-Fc, were depleted. Importantly, there was no phagocytosis of CV1 monomer-coengineered T cells by human macrophages. Moreover, avelumab and cetuximab enhanced macrophage-mediated phagocytosis of tumor cells in vitro in the presence of CV1 and improved tumor control upon coadministration with A97L-T cells. Taken together, our study indicates important clinical promise for harnessing macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells.


Asunto(s)
Macrófagos , Fagocitosis , Receptores Inmunológicos , Animales , Humanos , Ratones , Antígenos de Diferenciación/inmunología , Antígenos de Neoplasias/inmunología , Antígeno CD47/inmunología , Línea Celular Tumoral , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/genética , Inmunoterapia Adoptiva , Macrófagos/inmunología , Macrófagos/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Femenino
4.
Front Immunol ; 15: 1395684, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38868776

RESUMEN

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.


Asunto(s)
Anticuerpos Antivirales , Linfocitos B , COVID-19 , Receptores Inmunológicos , SARS-CoV-2 , Células T Auxiliares Foliculares , Humanos , COVID-19/inmunología , Receptores Inmunológicos/inmunología , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Masculino , Células T Auxiliares Foliculares/inmunología , Linfocitos B/inmunología , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Persona de Mediana Edad , Adulto , Activación de Linfocitos/inmunología , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre
5.
Nature ; 630(8016): 457-465, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38750365

RESUMEN

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.


Asunto(s)
Antígeno CD47 , Macrófagos , Receptores Quiméricos de Antígenos , Receptores Inmunológicos , Linfocitos T , Microambiente Tumoral , Antígeno CD47/inmunología , Antígeno CD47/metabolismo , Animales , Ratones , Linfocitos T/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Humanos , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Femenino , Microambiente Tumoral/inmunología , Receptores Quiméricos de Antígenos/inmunología , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/metabolismo , Masculino
6.
Trends Immunol ; 45(6): 400-402, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38789321

RESUMEN

Miyamoto et al. report that Marco expression demarcates a population of IL-10-expressing immunosuppressive Kupffer cells (KCs) that are preferentially peri-portally located in the mouse liver, and which limit bacterial dissemination and liver inflammation.


Asunto(s)
Interleucina-10 , Macrófagos del Hígado , Hígado , Animales , Macrófagos del Hígado/inmunología , Ratones , Hígado/inmunología , Hígado/patología , Interleucina-10/metabolismo , Interleucina-10/inmunología , Humanos , Macrófagos/inmunología , Inflamación/inmunología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología
7.
Sci Immunol ; 9(95): eadi5374, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758808

RESUMEN

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.


Asunto(s)
Microbioma Gastrointestinal , Inmunoterapia , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Ratones , Microbioma Gastrointestinal/inmunología , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Macrófagos/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones Noqueados , Femenino , Intestinos/inmunología
8.
Sci Rep ; 14(1): 10661, 2024 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724599

RESUMEN

We report the generation of a novel anti-LAG-3/TIGIT bispecific IgG4 antibody, ZGGS15, and evaluated its anti-tumor efficacy in mouse models as monotherapy or in combination with a PD-1 antibody. ZGGS15 exhibited strong affinities for human LAG-3 and TIGIT, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 has EC50s of 0.69 nM and 1.87 nM for binding to human LAG-3 and TIGIT on CHO-K1 cells, respectively. ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50 = 0.24 nM). ZGGS15 does not induce ADCC, CDC, or obvious cytokine production. In vivo results showed that ZGGS15 had better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agents and demonstrated a synergistic effect when combined with nivolumab, with a significantly higher tumor growth inhibition of 95.80% (p = 0.001). The tumor volume inhibition rate for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% (p < 0.001). Our data reveal that ZGGS15 exhibits potent anti-tumor efficacy without eliciting ADCC or CDC or causing cytokine production, therefore having a safe profile.


Asunto(s)
Anticuerpos Biespecíficos , Proteína del Gen 3 de Activación de Linfocitos , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Femenino , Humanos , Ratones , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD/inmunología , Antígenos CD/metabolismo , Línea Celular Tumoral , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Clin Cancer Res ; 30(11): 2300-2302, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38568191

RESUMEN

Outcomes in mature T-cell lymphomas remain poor, with previous attempts at developing mAbs compromised by limited efficacy and significant immunocompromise. Anti-killer cell lectin-like receptor G1 mAbs may have greater selectivity and specificity for malignant T cells and avoid the toxicity concerns with previous agents. See related article by Assatova et al., p. 2514.


Asunto(s)
Lectinas Tipo C , Humanos , Lectinas Tipo C/inmunología , Lectinas Tipo C/metabolismo , Lectinas Tipo C/antagonistas & inhibidores , Linfoma de Células T/patología , Linfoma de Células T/tratamiento farmacológico , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico
10.
Nature ; 628(8009): 854-862, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38570678

RESUMEN

The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.


Asunto(s)
Mucosa Intestinal , Membrana Mucosa , Linfocitos T Reguladores , Animales , Femenino , Masculino , Ratones , Antígenos CD/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Helicobacter hepaticus/inmunología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Cadenas alfa de Integrinas/metabolismo , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Análisis de Expresión Génica de una Sola Célula , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/citología , Transcriptoma
11.
Cancer Res ; 84(12): 1978-1995, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38635895

RESUMEN

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.


Asunto(s)
Receptores Inmunológicos , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Ratones , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Femenino , Linfocitos T CD8-positivos/inmunología , Ratones Endogámicos C57BL , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico
12.
Curr Med Chem ; 31(13): 1634-1645, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38666504

RESUMEN

Immune checkpoint inhibitors (ICIs) have shown unprecedented efficacy in treating many advanced cancers. Although FDA-approved ICIs have shown promising efficacy in treating many advanced cancers, their application is greatly limited by the low response rate, immune-related adverse events (irAE), and drug resistance. Developing novel ICIs holds great promise to improve the survival and prognosis of advanced cancer patients. T-Cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on T cells, natural killer (NK) cells, and T regulatory cells. Increasing reports have shown that the disrupting CD155-TIGIT axis could activate the immune system and restore antitumor immune response. This review briefly summarized the role of TIGIT in tumor immune escape and targeting CD155-TIGIT axis drugs in preclinical and clinical trials for cancer immunotherapy.


Asunto(s)
Inmunoterapia , Neoplasias , Receptores Inmunológicos , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Receptores Virales/metabolismo , Receptores Virales/antagonistas & inhibidores , Receptores Virales/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Animales
13.
Int Immunopharmacol ; 133: 112055, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38677094

RESUMEN

As a transmembrane protein, CD300e is primarily expressed in myeloid cells. It belongs to the CD300 glycoprotein family, functioning as an immune-activating receptor. Dysfunction of CD300e has been suggested in many diseases, such as infections, immune disorders, obesity, and diabetes, signifying its potential as a key biomarker for disease diagnosis and treatment. This review is aimed to explore the roles and potential mechanisms of CD300e in regulating oxidative stress, immune cell activation, tissue damage and repair, and lipid metabolism, shedding light on its role as a diagnostic marker or a therapeutic target, particularly for infections and autoimmune disorders.


Asunto(s)
Receptores Inmunológicos , Humanos , Animales , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Estrés Oxidativo , Metabolismo de los Lípidos , Enfermedades Autoinmunes/inmunología , Antígenos CD/metabolismo , Antígenos CD/inmunología , Biomarcadores
14.
Eur J Immunol ; 54(6): e2350771, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38494423

RESUMEN

Vomocytosis, also known as nonlytic exocytosis, is a process whereby fully phagocytosed microbes are expelled from phagocytes without discernible damage to either the phagocyte or microbe. Although this phenomenon was first described in the opportunistic fungal pathogen Cryptococcus neoformans in 2006, to date, mechanistic studies have been hampered by an inability to reliably stimulate or inhibit vomocytosis. Here we present the fortuitous discovery that macrophages lacking the scavenger receptor MAcrophage Receptor with COllagenous domain (MARCO), exhibit near-total vomocytosis of internalised cryptococci within a few hours of infection. Marco-/- macrophages also showed elevated vomocytosis of a yeast-locked C. albicans strain, suggesting this to be a broadly relevant observation. We go on to show that MARCO's role in modulating vomocytosis is independent of its role as a phagocytic receptor, suggesting that this protein may play an important and hitherto unrecognised role in modulating macrophage behaviour.


Asunto(s)
Cryptococcus neoformans , Macrófagos , Receptores Inmunológicos , Animales , Ratones , Cryptococcus neoformans/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/genética , Candida albicans/inmunología , Fagocitosis/inmunología , Ratones Noqueados , Exocitosis/inmunología , Criptococosis/inmunología
15.
Int Immunol ; 36(7): 365-371, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38442194

RESUMEN

The intestinal barrier consists of mucosal, epithelial, and immunological barriers and serves as a dynamic interface between the host and its environment. Disruption of the intestinal barrier integrity is a leading cause of various gastrointestinal diseases, such as inflammatory bowel disease. The homeostasis of the intestinal barrier is tightly regulated by crosstalk between gut microbes and the immune system; however, the implication of the immune system on the imbalance of gut microbes that disrupts barrier integrity remains to be fully elucidated. An inhibitory immunoglobulin-like receptor, Allergin-1, is expressed on mast cells and dendritic cells and inhibits Toll-like receptor (TLR)-2 and TLR-4 signaling in these cells. Since TLRs are major sensors of microbiota and are involved in local epithelial homeostasis, we investigated the role of Allergin-1 in maintaining intestinal homeostasis. Allergin-1-deficient (Milr1-/-) mice exhibited more severe dextran sulfate sodium (DSS)-induced colitis than did wild-type (WT) mice. Milr1-/- mice showed an enhanced intestinal permeability compared with WT mice even before DSS administration. Treatment of Milr1-/- mice with neomycin, but not ampicillin, restored intestinal barrier integrity. The 16S rRNA gene sequencing analysis demonstrated that Bifidobacterium pseudolongum was the dominant bacterium in Milr1-/- mice after treatment with ampicillin. Although the transfer of B. pseudolongum to germ-free WT mice had no effect on intestinal permeability, its transfer into ampicillin-treated WT mice enhanced intestinal permeability. These results demonstrated that Allergin-1 deficiency enhanced intestinal dysbiosis with expanded B. pseudolongum, which contributes to intestinal barrier dysfunction in collaboration with neomycin-sensitive and ampicillin-resistant microbiota.


Asunto(s)
Disbiosis , Mucosa Intestinal , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Disbiosis/inmunología , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/metabolismo , Sulfato de Dextran , Microbioma Gastrointestinal/inmunología , Colitis/inmunología , Colitis/microbiología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Neomicina/farmacología , Permeabilidad
16.
Cancer Biol Med ; 21(4)2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38425216

RESUMEN

OBJECTIVE: The human cluster of differentiation (CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer (NK) cells targeting hematologic malignancies (HMs). METHODS: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine (PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients. RESULTS: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS-CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an "exhausted" phenotype of intratumoral NK cells in patients with HMs or solid tumors. CONCLUSIONS: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.


Asunto(s)
Neoplasias Hematológicas , Células Asesinas Naturales , Receptores Inmunológicos , Humanos , Células Asesinas Naturales/inmunología , Animales , Ratones , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Antígenos CD/metabolismo , Antígenos CD/inmunología , Masculino , Línea Celular Tumoral , Citotoxicidad Inmunológica , Fosfatidilserinas/metabolismo
17.
Nature ; 627(8005): 847-853, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38480885

RESUMEN

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain mediate recognition of strain-specific pathogen effectors, typically via their C-terminal ligand-sensing domains1. Effector binding enables TIR-encoded enzymatic activities that are required for TIR-NLR (TNL)-mediated immunity2,3. Many truncated TNL proteins lack effector-sensing domains but retain similar enzymatic and immune activities4,5. The mechanism underlying the activation of these TIR domain proteins remain unclear. Here we show that binding of the TIR substrates NAD+ and ATP induces phase separation of TIR domain proteins in vitro. A similar condensation occurs with a TIR domain protein expressed via its native promoter in response to pathogen inoculation in planta. The formation of TIR condensates is mediated by conserved self-association interfaces and a predicted intrinsically disordered loop region of TIRs. Mutations that disrupt TIR condensates impair the cell death activity of TIR domain proteins. Our data reveal phase separation as a mechanism for the activation of TIR domain proteins and provide insight into substrate-induced autonomous activation of TIR signalling to confer plant immunity.


Asunto(s)
Adenosina Trifosfato , Arabidopsis , NAD , Nicotiana , Separación de Fases , Proteínas de Plantas , Dominios Proteicos , Adenosina Trifosfato/metabolismo , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/inmunología , Proteínas de Arabidopsis/metabolismo , Muerte Celular , Mutación , NAD/metabolismo , Nicotiana/genética , Nicotiana/inmunología , Nicotiana/metabolismo , Proteínas NLR/química , Proteínas NLR/genética , Proteínas NLR/inmunología , Proteínas NLR/metabolismo , Enfermedades de las Plantas/inmunología , Inmunidad de la Planta/genética , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/inmunología , Proteínas de Plantas/metabolismo , Regiones Promotoras Genéticas , Dominios Proteicos/genética , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal , Receptores Toll-Like/química , Receptores de Interleucina-1/química
18.
Nature ; 627(8004): 646-655, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38418879

RESUMEN

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.


Asunto(s)
Anticuerpos Monoclonales , Antineoplásicos , Antígeno B7-H1 , Células Mieloides , Neoplasias , Receptores Inmunológicos , Linfocitos T Reguladores , Animales , Humanos , Ratones , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Quimioterapia Combinada , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Activación de Macrófagos , Células Mieloides/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores de IgG/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología
19.
Cancer Res ; 84(10): 1550-1559, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38381555

RESUMEN

Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes. SIGNIFICANCE: Lipid nanoparticle-encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity.


Asunto(s)
Nanopartículas , ARN Mensajero , Proteínas Recombinantes de Fusión , Animales , Ratones , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/inmunología , Nanopartículas/química , Humanos , Femenino , Ratones Endogámicos C57BL , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/genética , Lípidos/química , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Línea Celular Tumoral
20.
Clin Cancer Res ; 30(11): 2514-2530, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38252421

RESUMEN

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.


Asunto(s)
Lectinas Tipo C , Receptores Inmunológicos , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Ratones , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/inmunología , Lectinas Tipo C/metabolismo , Lectinas Tipo C/inmunología , Lectinas Tipo C/antagonistas & inhibidores , Línea Celular Tumoral , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Linfoma de Células T/terapia , Linfoma de Células T/tratamiento farmacológico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología
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