RESUMEN
SLAMF9, a member of the conserved lymphocyte activation molecules family (SLAMF), has been less investigated compared to other SLAMs, especially concerning its implications across various cancer types. In our systematic pan-cancer investigation, we observed elevated SLAMF9 expression in various tumor tissues, which was correlated with reduced patient survival across most malignancies. Correlation analyses further revealed significant associations between SLAMF9 expression and immune cell infiltrates, immune checkpoint inhibitors, tumor mutation load, microsatellite instability, and epithelial-mesenchymal transition (EMT) scores. Cell-based assays demonstrated that SLAMF9 knockdown attenuated the proliferative, motile, and invasive capacities of colorectal cancer (CRC) cells. In a nude mouse xenograft model, suppression of SLAMF9 expression substantially inhibited tumor growth. These findings highlight the potential of SLAMF9 as a prognostic and therapeutic biomarker across tumors, with notable implications for CRC cell proliferation and migration.
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Proliferación Celular , Neoplasias Colorrectales , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Animales , Femenino , Humanos , Ratones , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Inestabilidad de Microsatélites , Pronóstico , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genéticaRESUMEN
PURPOSE OF REVIEW: In this review, we provide an overview of the current understanding of SLAM-family receptors in hematologic malignancies. We highlighted their contribution to the disease pathogenesis and targeting strategies to improve therapeutic outcomes. RECENT FINDINGS: Emerging studies have reported the tumor-promoting role of SLAM-family receptors in various hematologic malignancies, including chronic lymphocytic leukemia, acute myeloid leukemia, and multiple myeloma. Specifically, they regulate the interaction between malignant cells and the tumor microenvironment to promote apoptosis resistance, therapeutic resistance, impairment of antitumor and tumor progression. SUMMARY: SLAM-family receptors promote the progression of hematologic malignancies by regulating the interaction between malignant cells and the tumor microenvironment. This provides the rationale that SLAM-targeted therapies are appealing strategies to enhance therapeutic outcomes in patients.
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Neoplasias Hematológicas , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Humanos , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/tratamiento farmacológico , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Microambiente Tumoral , Transducción de Señal , AnimalesRESUMEN
Natural Killer (NK) cells have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). NK cell activation is tightly regulated by the engagement of its inhibitory and activating receptors. The activating receptor CD16 drives ADCC upon binding to the Fc portion of antibodies; NK cell activation is further sustained by the co-engagement of activating receptors NTB-A and 2B4. During HIV-1 infection, Nef and Vpu accessory proteins contribute to ADCC escape by downregulating the ligands of NTB-A and 2B4. HIV-1 also evades ADCC by keeping its envelope glycoproteins (Env) in a "closed" conformation which effectively masks epitopes recognized by non-neutralizing antibodies (nnAbs) which are abundant in the plasma of people living with HIV. To achieve this, the virus uses its accessory proteins Nef and Vpu to downregulate the CD4 receptor, which otherwise interacts with Env and exposes the epitopes recognized by nnAbs. Small CD4-mimetic compounds (CD4mc) have the capacity to expose these epitopes, thus sensitizing infected cells to ADCC. Given the central role of NK cell co-activating receptors NTB-A and 2B4 in Fc-effector functions, we studied their contribution to CD4mc-mediated ADCC. Despite the fact that their ligands are partially downregulated by HIV-1, we found that both co-activating receptors significantly contribute to CD4mc sensitization of HIV-1-infected cells to ADCC.
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Citotoxicidad Celular Dependiente de Anticuerpos , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Células Asesinas Naturales , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Humanos , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , VIH-1/inmunología , Células Asesinas Naturales/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Antígenos CD4/inmunología , Antígenos CD4/metabolismo , Proteínas del Virus de la Inmunodeficiencia Humana/inmunología , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/metabolismo , Proteínas Reguladoras y Accesorias Virales/metabolismo , Proteínas Reguladoras y Accesorias Virales/inmunología , Proteínas Reguladoras y Accesorias Virales/genética , Anticuerpos Neutralizantes/inmunología , Proteínas ViroporinasRESUMEN
Birdshot chorioretinopathy is an inflammatory eye condition strongly associated with MHC-I allele HLA-A29. The striking association with MHC-I suggests involvement of T cells, whereas natural killer (NK) cell involvement remains largely unstudied. Here we show that HLA-A29-positive birdshot chorioretinopathy patients have a skewed NK cell pool containing expanded CD16 positive NK cells which produce more proinflammatory cytokines. These NK cells contain populations that express CD8A which is involved in MHC-I recognition on target cells, display gene signatures indicative of high cytotoxic activity (GZMB, PRF1 and ISG15), and signaling through NK cell receptor CD244 (SH2D1B). Long-term monitoring of a cohort of birdshot chorioretinopathy patients with active disease identifies a population of CD8bright CD244bright NK cells, which rapidly declines to normal levels upon clinical remission following successful treatment. Collectively, these studies implicate CD8bright CD244bright NK cells in birdshot chorioretinopathy.
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Retinocoroidopatía en Perdigonada , Antígenos HLA-A , Células Asesinas Naturales , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Análisis de la Célula Individual , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Retinocoroidopatía en Perdigonada/inmunología , Retinocoroidopatía en Perdigonada/metabolismo , Antígenos HLA-A/genética , Antígenos HLA-A/metabolismo , Antígenos HLA-A/inmunología , Análisis de la Célula Individual/métodos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Antígenos CD8/metabolismo , Antígenos CD8/genética , Coriorretinitis/inmunología , Coriorretinitis/genética , Femenino , Receptores de IgG/metabolismo , Receptores de IgG/genética , Masculino , Citocinas/metabolismo , Adulto , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/genética , Persona de Mediana Edad , PerforinaRESUMEN
BACKGROUND: Autologous BCMA-specific CAR T-cell therapies have substantial activity in multiple myeloma (MM). However, due to logistical limitations and BCMAlow relapses, there is a need for alternatives. UCARTCS1 cells are 'off-the-shelf' allogeneic CAR T-cells derived from healthy donors targeting SLAMF7 (CS1), which is highly expressed in MM cells. In this study, we evaluated the preclinical activity of UCARTCS1 in MM cell lines, in bone marrow (BM) samples obtained from MM patients and in an MM mouse model. METHODS: Luciferase-transduced MM cell lines were incubated with UCARTCS1 cells or control (non-transduced, SLAMF7/TCRαß double knock-out) T-cells at different effector to target ratios for 24 hours. MM cell lysis was assessed by bioluminescence. Anti-MM activity of UCARTCS1 was also evaluated in 29 BM samples obtained from newly diagnosed patients (n=10), daratumumab-naïve relapsed/refractory patients (n=10) and daratumumab-refractory patients (n=9) in 24-hour flow cytometry-based cytotoxicity assays. Finally, UCARTCS1 activity was assessed in mouse xenograft models. RESULTS: UCARTCS1 cells induced potent CAR-mediated, and dose-dependent lysis of both MM cell lines and primary MM cells. There was no difference in ex vivo activity of UCARTCS1 between heavily pretreated and newly diagnosed patients. In addition, efficacy of UCARTCS1 was not affected by SLAMF7 expression level on MM cells, proportion of tumor cells, or frequency of regulatory T-cells in BM samples obtained from MM patients. UCARTCS1 treatment eliminated SLAMF7+ non-malignant immune cells in a dose-dependent manner, however lysis of normal cells was less pronounced compared to that of MM cells. Additionally, durable anti-MM responses were observed with UCARTCS1 in an MM xenograft model. CONCLUSIONS: These results demonstrate that UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in an MM xenograft model and support the evaluation of UCARTCS1 in patients with advanced MM.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Humanos , Animales , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Ratones , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Línea Celular TumoralRESUMEN
INTRODUCTION: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care. AREAS COVERED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. EXPERT OPINION: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.
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Factor de Transcripción Ikaros , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Factor de Transcripción Ikaros/metabolismo , Talidomida/uso terapéutico , Talidomida/análogos & derivados , Talidomida/farmacología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Proteolisis/efectos de los fármacos , Terapia Molecular Dirigida , Agentes Inmunomoduladores/uso terapéutico , Agentes Inmunomoduladores/farmacología , Ensayos Clínicos como Asunto , Animales , Piperidonas , Morfolinas , Receptores de Interleucina-17 , Proteínas Adaptadoras Transductoras de Señales , FtalimidasRESUMEN
Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.
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Inmunidad Innata , Inflamación , Pulmón , Linfocitos , Ratones Endogámicos C57BL , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Animales , Ratones , Inflamación/inmunología , Inflamación/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Pulmón/inmunología , Pulmón/patología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Papaína , Células Th2/inmunología , Interleucina-13/metabolismo , Interleucina-13/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Interleucina-33/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Noqueados , Transducción de Señal , FN-kappa B/metabolismoRESUMEN
ABSTRACT: The identification and targeting of B-cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates, chimeric antigen receptor T cells, and T-cell engagers have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved the survival outcomes of patients with relapsed and/or refractory MM compared with previously established strategies and are moving into earlier lines of therapy. Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvage. G-protein-coupled receptor class 5 member D, Fc receptor-homolog 5, and SLAMF7 are some examples of novel targets in development. This expanding armamentarium of immunotherapeutic agents will be crucial to address the unmet need for relapses after BCMA-targeting therapies, particularly antigen-negative relapses. The utilization of sequential T-cell redirective therapies including agents targeting different tumor-associated antigens and combination therapies appears feasible, paving the way for effective chemotherapy-free regimes. Deliberate consideration of treatment timing, preserving T-cell health, overcoming antigenic loss, and comprehension of the complex tumor microenvironment would be key to maximizing therapeutic benefits and minimizing adverse effects. This review summarizes novel targets in development for myeloma beyond BCMA, presenting pivotal safety and efficacy data derived from clinical trials when available and the considerations vital for navigating this expanding landscape of immunotherapeutic options.
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Antígeno de Maduración de Linfocitos B , Mieloma Múltiple , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Humanos , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/inmunología , Inmunoterapia/métodos , Terapia Molecular Dirigida , Linfocitos T/inmunología , Linfocitos T/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/antagonistas & inhibidores , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
Introduction: Multiple myeloma (MM) remains incurable, despite the advent of chimeric antigen receptor (CAR)-T cell therapy. This unfulfilled potential can be attributed to two untackled issues: the lack of suitable CAR targets and formats. In relation to the former, the target should be highly expressed and reluctant to shedding; two characteristics that are attributed to the CS1-antigen. Furthermore, conventional CARs rely on scFvs for antigen recognition, yet this withholds disadvantages, mainly caused by the intrinsic instability of this format. VHHs have been proposed as valid scFv alternatives. We therefore intended to develop VHH-based CAR-T cells, targeting CS1, and to identify VHHs that induce optimal CAR-T cell activation together with the VHH parameters required to achieve this. Methods: CS1-specific VHHs were generated, identified and fully characterized, in vitro and in vivo. Next, they were incorporated into second-generation CARs that only differ in their antigen-binding moiety. Reporter T-cell lines were lentivirally transduced with the different VHH-CARs and CAR-T cell activation kinetics were evaluated side-by-side. Affinity, cell-binding capacity, epitope location, in vivo behavior, binding distance, and orientation of the CAR-T:MM cell interaction pair were investigated as predictive parameters for CAR-T cell activation. Results: Our data show that the VHHs affinity for its target antigen is relatively predictive for its in vivo tumor-tracing capacity, as tumor uptake generally decreased with decreasing affinity in an in vivo model of MM. This does not hold true for their CAR-T cell activation potential, as some intermediate affinity-binding VHHs proved surprisingly potent, while some higher affinity VHHs failed to induce equal levels of T-cell activation. This could not be attributed to cell-binding capacity, in vivo VHH behavior, epitope location, cell-to-cell distance or binding orientation. Hence, none of the investigated parameters proved to have significant predictive value for the extent of CAR-T cell activation. Conclusions: We gained insight into the predictive parameters of VHHs in the CAR-context using a VHH library against CS1, a highly relevant MM antigen. As none of the studied VHH parameters had predictive value, defining VHHs for optimal CAR-T cell activation remains bound to serendipity. These findings highlight the importance of screening multiple candidates.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Anticuerpos de Dominio Único , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Humanos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Anticuerpos de Dominio Único/inmunología , Inmunoterapia Adoptiva/métodos , Animales , Línea Celular Tumoral , Ratones , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Anticuerpos de Cadena Única/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The effectiveness of immune checkpoint inhibitor (ICI) therapy is hindered by the ineffective infiltration and functioning of cytotoxic T cells and the immunosuppressive tumor microenvironment (TME). Signaling lymphocytic activation molecule family member 7 (SLAMF7) is a pivotal co-stimulatory receptor thought to simultaneously trigger NK-cell, T-cell, and macrophage antitumor cytotoxicity. However, the potential of this collaborative immune stimulation in antitumor immunity for solid tumors is underexplored due to the exclusive expression of SLAMF7 by hematopoietic cells. Here, we report the development and characterization of multifunctional bispecific nanovesicles (NVs) targeting SLAMF7 and glypican-3-a hepatocellular carcinoma (HCC)-specific tumor antigen. We found that by effectively "decorating" the surfaces of solid tumors with SLAMF7, these NVs directly induced potent and specific antitumor immunity and remodeled the immunosuppressive TME, sensitizing the tumors to programmed cell death protein 1 (PD1) blockade. Our findings highlight the potential of SLAMF7-targeted multifunctional bispecific NVs as an anticancer strategy with implications for designing next-generation targeted cancer therapies.
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Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Microambiente Tumoral , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/antagonistas & inhibidores , Humanos , Animales , Ratones , Microambiente Tumoral/inmunología , Nanopartículas/química , Línea Celular Tumoral , Anticuerpos Biespecíficos/farmacología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Inmunoterapia/métodos , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
SLAMF8, the eighth member of the Signaling Lymphocytic Activation Molecule Family (SLAMF), functions in the regulation of the development and activity of diverse immune cells as a costimulatory receptor within the SLAMF family. Studies had revealed that SLAMF8 is expressed higher in several autoimmune inflammation diseases and tumors. Nevertheless, the connection between SLAMF8 and pan-cancer remains undisclosed. The research investigated the correlation between SLAMF8 and various factors including the immune microenvironment, microsatellite instability, immune novel antigen, gene mutation, immune regulatory factors, immune blockade TMB, and immune or molecular subtypes of SLAMF8 in verse cancer types. Immunohistochemistry was ultimately employed to validate the presence of the SLAMF8 gene in various tumor types including hepatocellular carcinoma, prostate adenocarcinoma, and kidney renal clear cell carcinoma. Furthermore, the relationship between SLAMF8 expression and the therapeutic efficacy of the PD1 blockade agent, Sintilimab, treatment in gastric cancer was validated. The result of differential analysis suggested that SLAMF8 was over-expressed in pan-cancer compared with paracancerous tissues. The analysis of survival indicated a connection between SLAMF8 and the overall prognosis in different types of cancers, where higher levels of SLAMF8 were found to be significantly linked to unfavorable outcomes in patients but favorable outcome of immunotherapy in gastric cancer. Significant correlations were observed between SLAMF8 levels and pan-cancer tumorigenesis, tumor metabolism, and immunity. As a result, SLAMF8 may become an important prognostic biomarker in the majority of tumors and a hopeful gene target for immunotherapy against gastric cancer.
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Inmunoterapia , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Inmunoterapia/métodos , Pronóstico , Microambiente Tumoral/inmunología , Masculino , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión GénicaRESUMEN
Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically, P. anaerobius administration activated integrin α2ß1-NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2+ MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC_22, a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally, therapeutic targeting of either integrin α2ß1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC.
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Neoplasias Colorrectales , Células Supresoras de Origen Mieloide , Receptor de Muerte Celular Programada 1 , Animales , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Ratones , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/microbiología , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Humanos , Línea Celular Tumoral , Integrina alfa2beta1/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Resistencia a Antineoplásicos , Modelos Animales de Enfermedad , Femenino , FN-kappa B/metabolismoRESUMEN
Immunoglobulin A (IgA) is the predominant mucosal antibody class with both anti- and pro-inflammatory roles1-3. However, the specific role of the IgA receptor cluster of differentiation (CD)89, expressed by a subset of natural killer (NK) cells, is poorly explored. We found that CD89 protein expression on circulating NK cells is infrequent in humans and rhesus macaques, but transcriptomic analysis showed ubiquitous CD89 expression, suggesting an inducible phenotype. Interestingly, CD89+ NK cells were more frequent in cord blood and mucosae, indicating a putative IgA-mediated NK cell function in the mucosae and infant immune system. CD89+ NK cells signaled through upregulated CD3 zeta chain (CD3ζ), spleen tyrosine kinase (Syk), zeta chain-associated protein kinase 70 (ZAP70), and signaling lymphocytic activation molecule family 1 (SLAMF1), but also showed high expression of inhibitory receptors such as killer cell lectin-like receptor subfamily G (KLRG1) and reduced activating NKp46 and NKp30. CD89-based activation or antibody-mediated cellular cytotoxicity with monomeric IgA1 reduced NK cell functions, while antibody-mediated cellular cytotoxicity with combinations of IgG and IgA2 was enhanced compared to IgG alone. These data suggest that functional CD89+ NK cells survey mucosal sites, but CD89 likely serves as regulatory receptor which can be further modulated depending on IgA and IgG subclass. Although the full functional niche of CD89+ NK cells remains unexplored, these intriguing data suggest the CD89 axis could represent a novel immunotherapeutic target in the mucosae or early life.
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Inmunoglobulina A , Células Asesinas Naturales , Macaca mulatta , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Receptores Fc/metabolismo , Receptores Fc/genética , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Regulación hacia Arriba , Inmunidad Mucosa , Citotoxicidad Inmunológica , Células Cultivadas , Antígenos CDRESUMEN
The signaling lymphocytic activation molecule (SLAM) family participates in the modulation of various innate and adaptive immune responses. SLAM family (SLAMF) receptors include nine transmembrane glycoproteins, of which SLAMF3 (also known as CD229 or Ly9) has important roles in the modulation of immune responses, from the fundamental activation and suppression of immune cells to the regulation of intricate immune networks. SLAMF3 is mainly expressed in immune cells, such as T, B, and natural killer cells. It has a unique molecular structure, including four immunoglobulin-like domains in the extracellular domain and two immunoreceptor tyrosine-based signaling motifs in the intracellular structural domains. These unique structures have important implications for protein functioning. SLAMF3 is involved in pathogenesis of various disease, particularly autoimmune diseases and cancer. However, despite its potential clinical significance, a comprehensive overview of the current paradigm of SLAMF3 research is lacking. This review summarizes the structure, functional mechanisms, and therapeutic implications of SLAMF3. Our findings highlight the significance of SLAMF3 in both physiological and pathological contexts, and underline its dual role in autoimmunity and malignancies, and including disease progression and prognosis. The review also proposes that future studies on SLAMF3 should explore its context-specific inhibitory and stimulatory effects, expand on its potential in disease mapping, investigate related signaling pathways, and explore its value as a drug target. Research in these areas related to SLAMF3 can provide more precise directions for future therapeutic strategies.
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Neoplasias , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Humanos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Animales , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapiaRESUMEN
Recently, cancer immunotherapy has revolutionized cancer treatment. Various forms of immunotherapy have a manageable safety profile and result in prolongation of overall survival in patients with solid tumors, but only in a proportion of patients. Various factors in the tumor microenvironment play critical roles and may be responsible for this lack of therapeutic response. Signaling lymphocytic activation molecule family (SLAMF) members are increasingly being studied as factors impacting the tumor immune microenvironment. SLAMF members consist of nine receptors mainly expressed in immune cells. However, SLAMF receptors have also been detected in cancer cells, and they may be involved in a spectrum of anti-tumor immune responses. Here, we review the current knowledge of the expression of SLAMF receptors in solid tumors and tumor-infiltrating immune cells and their association with patient outcomes. Furthermore, we discuss the therapeutic potential of targeting SLAMF receptors to improve outcomes of cancer therapy in solid tumors. We believe the research on SLAMF receptor-targeted strategies may enhance anti-cancer immunity in patients with solid tumors and improve clinical outcomes.
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Neoplasias , Humanos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Inmunoterapia , Microambiente TumoralRESUMEN
Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8+ T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization in vitro. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and CCL2 transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti-PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy. SIGNIFICANCE: CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients.
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Carcinoma Hepatocelular , Quimiocina CCL2 , Inmunoterapia , Neoplasias Hepáticas , Macrófagos , Ratones Noqueados , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Animales , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Humanos , Ratones , Inmunoterapia/métodos , Quimiocina CCL2/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Transducción de Señal , Ratones Endogámicos C57BL , Línea Celular TumoralRESUMEN
BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.
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Melanoma , Monocitos , Humanos , Animales , Ratones , Monocitos/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Macrófagos/metabolismo , Linfocitos T CD8-positivos , Carcinogénesis/metabolismo , Microambiente Tumoral , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
Compelling evidence shows that the frequency of T cells in the tumor microenvironment correlates with prognosis as well as response to immunotherapy. However, considerable heterogeneity exists within tumor-infiltrating T cells, and significance of their genomic and transcriptomic landscape on clinical outcomes remains to be elucidated. Signaling lymphocyte activation molecule 6 (SLAMF6) is expressed on intra-tumoral progenitor-exhausted T cells, which exhibit the capacity to proliferate, self-renew and produce terminally-exhausted T cells in pre-clinical models and patients. Here, we investigated the impact of SLAMF6 expression on prognosis in two immunologically different tumor types using publicly available databases. Our findings demonstrate that high SLAMF6 expression is associated with better prognosis, expression of TCF7 (encoding T-cell factor 1), and increased gene signatures associated with conventional type 1 dendritic cells and effector function of T cells in melanoma and breast cancer. Single-cell profiling of breast cancer tumor microenvironment reveals SLAMF6 expression overlaps CD8 T cells with a T-effector signature, which includes subsets expressing TCF7, memory and effector-related genes, analogous to progenitor-exhausted T cells. These findings illustrate the significance of SLAMF6 in the tumor as a marker for better effector responses, and provide insights into the predictive and prognostic determinants for cancer patients.
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Neoplasias de la Mama , Melanoma , Humanos , Femenino , Melanoma/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Microambiente Tumoral/genética , Linfocitos T CD8-positivos , Inmunoterapia , Pronóstico , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
Precise molecular characterization of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is hampered by their mixed composition of mature and immature cells and lack of specific markers. Here, we focus on mature CD66b+CD10+CD16+CD11b+ PMN-MDSCs (mPMN-MDSCs) from either cancer patients or healthy donors receiving G-CSF for stem cell mobilization (GDs). By RNA sequencing (RNA-seq) experiments, we report the identification of a distinct gene signature shared by the different mPMN-MDSC populations under investigation, also validated in mPMN-MDSCs from GDs and tumor-associated neutrophils (TANs) by single-cell RNA-seq (scRNA-seq) experiments. Analysis of such a gene signature uncovers a specific transcriptional program associated with mPMN-MDSC differentiation and allows us to identify that, in patients with either solid or hematologic tumors and in GDs, CD52, CD84, and prostaglandin E receptor 2 (PTGER2) represent potential mPMN-MDSC-associated markers. Altogether, our findings indicate that mature PMN-MDSCs distinctively undergo specific reprogramming during differentiation and lay the groundwork for selective immunomonitoring, and eventually targeting, of mature PMN-MDSCs.
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Células Supresoras de Origen Mieloide , Neoplasias , Humanos , Neutrófilos , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/patología , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Neoplasias/patología , Antígeno CD52/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
BACKGROUND: Myocardial infarction (MI) is a cardiovascular diseases, that seriously threatens human life. Signaling lymphocytic activation molecule family member 8 (SLAMF8) has been discovered to regulate the development and function of many immune cells. However, there are limited reports on SLAMF8 in the field of cardiopathy, and its regulatory role also remains unclear. METHODS: The mRNA and protein expressions of genes were examined through RT-qPCR and western blot. The infarct size in heart was assessed through TTC staining. The pathological section of heart tissue was evaluated through HE staining. The iron, Fe2+, MDA and SOD levels were assessed through the corresponding commercial kits. The ROS level was detected through Immunofluorescence (IF) staining. The cell viability and cell apoptosis were assessed through MTT assay and flow cytometry. RESULTS: Through GEO (GSE84796) database, SLAMF8 exhibited higher expression in heart failure patients. Furthermore, the ischemia/reperfusion SD rat (ischemia/reperfusion, I/R treatment) and H9C2 cell (hypoxia/reoxygenation, H/R treatment) models were set up. The mRNA and protein levels of SLAMF8 were upregulated in ischemia/reperfusion SD rat and H9C2 cell models. In addition, SLAMF8 inhibition alleviated ischemia/reperfusion-induced myocardial injury in SD rats. Moreover, SLAMF8 suppression inhibited ischemia/reperfusion-induced ferroptosis and oxidative stress. Further experiments were performed in H/R stimulated H9C2 cells, and the results showed that SLAMF8 knockdown alleviated H/R-induced cardiomyocyte death, ferroptosis and oxidative stress in H/R-induced cardiomyocyte. Lastly, SLAMF8 activated the TLR4/NOX4 pathway in I/R treated-SD rats or H/R treated-H9C2 cells. CONCLUSION: SLAMF8 aggravated ischemia/reperfusion-induced ferroptosis and injury in cardiomyocyte. This discovery may provide a useful bio-target for MI treatment.