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1.
Proc Natl Acad Sci U S A ; 114(23): 6086-6091, 2017 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-28533380

RESUMEN

The current study identifies CCR8+ regulatory T cells (Treg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of Treg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating Treg cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by Treg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8+ regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in Treg cells was further dissected through adoptive transfer studies using CCR8-/- mice. Collectively, we demonstrate the pivotal role of CCR8+ Treg cells in restraining immunity and highlight the potential clinical implications of this discovery.


Asunto(s)
Factores de Transcripción Forkhead/inmunología , Receptores CCR8/inmunología , Linfocitos T Reguladores/inmunología , Animales , Quimiocina CCL1/inmunología , Quimiocina CCL1/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Receptores CCR8/metabolismo , Linfocitos T Reguladores/metabolismo , Regulación hacia Arriba
2.
Cancer Immunol Immunother ; 67(12): 1949-1953, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30232521

RESUMEN

Bone marrow (BM) cells of the hematopoietic system, also known as BM-derived leukocytes (BMD), are mobilized from the BM to the blood and then colonize tumor sites. These cells then become key players in either promoting or regulating the development and progression of tumors. Among the cells that suppress anti-tumor immunity are regulatory T cells (Tregs), tumor-associated macrophages (TAMS) and myeloid-derived suppressor cells (MDSC). MDSC comprise CD11b+Gr1+Ly6Clow polymorphonuclear myeloid cells (PMN-MDSC), and CD11b+Gr1+Ly6Chigh monocytic myeloid cells (Mo-MDSC). Several studies including ours have identified the CCR2-CCL2 axis as the key driver of the mobilization of monocytic cells from the BM to the blood and later their colonization at the tumor site. The current review focuses on the mechanisms by which PMN-MDSC are mobilized from the BM to the blood and later to the tumor site, and their clinical implications.


Asunto(s)
Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Células Mieloides/metabolismo , Células Mieloides/patología , Neoplasias/metabolismo , Neoplasias/patología , Receptores CCR5/metabolismo , Animales , Biomarcadores , Humanos , Inmunomodulación , Células Mieloides/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/patología , Neoplasias/inmunología , Transducción de Señal , Microambiente Tumoral/inmunología
3.
Cytokine ; 109: 24-28, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29449068

RESUMEN

Chemokines are mostly known for their chemotactic properties, and less for their ability to direct the biological function of target cells, including T cells. The current review focuses on a key chemokine named CXCL10 and its role in directing the migratory propertied and biological function of CD4+ and CD8+ T cells in the context of cancer and inflammatory autoimmunity. CXCR3 is a chemokine receptor that is abundant on CD4+ T cells, CD8+ T cells and NK cells. It has three known ligands: CXCL9, CXCL10 and CXCL11. Different studies, including those coming form our laboratory, indicated that aside of attracting CD8+ and CD4+ effector T cells to tumor sites and sites of inflammation CXCL10 directs the polarization and potentiates the biological function of these cells. This makes CXCL10 a "key driver chemokine" and a valid target for therapy of autoimmune diseases such as Inflammatory Bowl's Disease, Multiple Sclerosis, Rheumatoid arthritis and others. As for cancer this motivated different groups, including our group to develop CXCL10 based therapies for cancer due to its ability to enhance T-dependent anti cancer immunity. The current review summarizes these findings and their potential translational implication.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL10/metabolismo , Quimiotaxis/inmunología , Neoplasias/patología , Animales , Humanos , Inflamación/inmunología , Ratones
4.
Mol Ther ; 25(2): 456-464, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28109957

RESUMEN

Chimeric major histocompatibility complex (MHC) molecules supplemented with T cell receptor (TCR) signaling motifs function as activation receptors and can redirect gene-modified T cells against pathogenic CD8 T cells. We have shown that ß2 microglobulin (ß2m) operates as a universal signaling component of MHC-I molecules when fused with the CD3-ζ chain. Linking the H-2Kd-binding insulin B chain peptide insulin B chain, amino acids 15-23 (InsB15-23) to the N terminus of ß2m/CD3-ζ, redirected polyclonal CD8 T cells against pathogenic CD8 T cells in a peptide-specific manner in the non-obese diabetic (NOD) mouse. Here, we describe mRNA electroporation for delivering peptide/ß2m/CD3-ζ genes to a reporter T cell line and purified primary mouse CD8 T cells. The peptide/ß2m/CD3-ζ products paired with endogenous MHC-I chains and transmitted strong activation signals upon MHC-I cross-linking. The reporter T cell line transfected with InsB15-23/ß2m/CD3-ζ mRNA was activated by an InsB15-23-H-2Kd-specific CD8 T cell hybrid only when the transfected T cells expressed H-2Kd. Primary NOD CD8 T cells expressing either InsB15-23/ß2m/CD3-ζ or islet-specific glucose-6-phosphatase catalytic subunit-related protein, amino acids 206-214 (IGRP206-214)/ß2m/CD3-ζ killed their respective autoreactive CD8 T cell targets in vitro. Furthermore, transfer of primary CD8 T cells transfected with InsB15-23/ß2m/CD3-ζ mRNA significantly reduced insulitis and protected NOD mice from diabetes. Our results demonstrate that mRNA encoding chimeric MHC-I receptors can redirect effector CD8 against diabetogenic CD8 T cells, offering a new approach for the treatment of type 1 diabetes.


Asunto(s)
Traslado Adoptivo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Inmunomodulación , ARN Mensajero/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Citotoxicidad Inmunológica , Diabetes Mellitus Tipo 1/prevención & control , Diabetes Mellitus Tipo 1/terapia , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Orden Génico , Vectores Genéticos/genética , Insulina/inmunología , Ratones , Ratones Endogámicos NOD , Complejo Receptor-CD3 del Antígeno de Linfocito T/genética , Proteínas Recombinantes de Fusión/genética , Transfección , Microglobulina beta-2/genética
5.
Inflamm Res ; 65(4): 285-94, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26794621

RESUMEN

OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.


Asunto(s)
Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Heparitina Sulfato/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Animales , Línea Celular Tumoral , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/tratamiento farmacológico , Hipersensibilidad Tardía/inmunología , Rodamiento de Leucocito/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Proteína Básica de Mielina/inmunología , Oxazolona , Ratas , Ratas Endogámicas Lew , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Resultado del Tratamiento , Ácido Trinitrobencenosulfónico
8.
Nanoscale Horiz ; 9(2): 295-304, 2024 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-38086653

RESUMEN

Cancer immunotherapy has received increasing attention in tumor therapy. However, insufficient infiltration of T cells and over-expressed PD-L1 checkpoint in tumor cells severely impede cancer immunotherapy. Here, an injectable hydrogel was designed to reinforce T cell infiltration and inactivate PD-L1 for powerful cancer immunotherapy. The hydrogel was created by sodium alginate (SA) as the gelator, where linagliptin particles and BMS-202 particles were present in hydrogel micropores. After gelation in the tumor site, the linagliptin powerfully suppressed chemokine CXCL10 degradation, enabling the introduced CXCL10 to realize sustainable chemotaxis towards strong T cell infiltration. Meanwhile, the BMS-202 inactivated PD-L1 of tumor cells, thereby eliminating the PD-L1-governed immune evasion. Therefore, the hydrogel in combination with CXCL10 demonstrated powerful cancer immunotherapy against primary and distant tumors, along with efficient inhibition of lung metastasis. Our study not only offers a potent platform against tumors, but also provides a conceptually new approach to reinforce cancer immunotherapy.


Asunto(s)
Neoplasias Pulmonares , Linfocitos T , Humanos , Linfocitos T/metabolismo , Antígeno B7-H1/metabolismo , Hidrogeles , Evasión Inmune , Linagliptina , Neoplasias Pulmonares/terapia , Inmunoterapia
9.
ACS Nano ; 17(11): 10376-10392, 2023 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-37194951

RESUMEN

Owing to the insidious onset of ovarian cancer, most patients are in the advanced stage with extensive peritoneal metastasis when they are diagnosed. Treatment of peritoneal metastasis from advanced ovarian cancer remains a significant challenge. Inspired by the massive macrophages in the peritoneal environment, here, we reported an artificial exosome-based peritoneal-localized hydrogel to domesticate peritoneal macrophages as the therapeutic target for realizing potent ovarian cancer therapy, where artificial exosomes derived from genetically sialic-acid-binding Ig-like lectin 10 (Siglec-10)-engineered M1-type macrophages were chemically designed as gelator. Upon triggering immunogenicity with X-ray radiation, our hydrogel encapsulating efferocytosis inhibitor MRX-2843 enabled a cascade regulation to orchestrate polarization, efferocytosis, and phagocytosis of peritoneal macrophages for realizing robust phagocytosis of tumor cells and powerful antigen presentation, offering a potent approach for ovarian cancer therapy via bridging the innate effector function of macrophages with their adaptive immune response. Moreover, our hydrogel is also applicable for potent treatment of inherent CD24-overexpressed triple-negative breast cancer, providing an emerging therapeutic regimen for the most lethal malignancies in women.


Asunto(s)
Exosomas , Neoplasias Ováricas , Neoplasias Peritoneales , Humanos , Femenino , Exosomas/patología , Hidrogeles , Macrófagos , Neoplasias Ováricas/tratamiento farmacológico
10.
J Immunol ; 185(4): 2589-99, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20639487

RESUMEN

CCR5 is a key CCR that is highly expressed on CD4(+) T cells. It binds three different ligands: CCL3 (MIP-alpha), CCL4 (MIP-beta), and CCL5 (RANTES). Recent studies suggested that the interaction between CCR5 and its ligands is essential not only for attracting these CCR5(+) T cells but also substantial for transuding cosignals for their activation. The current study explores, for the first time, the in vivo consequences of CCR5 as a costimulatory molecule. First, we show redundancy between CCR5 ligands not only in chemoattractive properties but also in their ability to induced cosignals via CCR5. This has motivated us to generate a soluble receptor-based fusion protein that would selectively bind and neutralize all three CCR5 ligands. We show in this study that a 30-aa-based CCR5-Ig fusion protein encoding the second extracellular domain of receptor selectively binds and neutralizes all three CCR5 ligands and, when administered during ongoing experimental autoimmune encephalomyelitis, rapidly suppressed the disease while arresting Ag-specific effector T cell functions. Finally, our results clearly show that although CCR5 ligands induced cosignaling for IL-2 production is directed by CCR5, other proinflammatory properties of these ligands, such as TNF-alpha, IL-17, and IFN-gamma production, are CCR5 independent and therefore likely to be mediated by the other receptors for these ligands. These findings imply that implementing a CCR5-Ig-based therapy would be advantageous over blockade of this receptor or of the use of mAbs for targeting a single CCR5 ligand.


Asunto(s)
Quimiocinas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Proteínas Recombinantes de Fusión/inmunología , Transducción de Señal/inmunología , Animales , Sitios de Unión/genética , Proliferación Celular , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Inmunoglobulinas/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Receptores CCR5/genética , Receptores CCR5/inmunología , Receptores CCR5/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Transducción de Señal/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo
11.
J Immunol ; 184(2): 1092-101, 2010 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-19995900

RESUMEN

We have previously shown that, during inflammatory autoimmune diseases in humans, the immune system develops a neutralizing auto-Ab-based response to a very limited number of inflammatory mediators, and that amplification of each response could be beneficial for the host. Our working hypothesis has been that this selective breakdown of immunological tolerance is due to a predominant expression of an inflammatory mediator at an immune-restricted site undergoing a destructive process. All three conditions also take place in cancer diseases. In this study, we delineate this hypothesis for the first time in a human cancer disease and then explore its clinical implications. We show that in primary tumor sections of prostate cancer subjects, CCL2 is predominantly expressed at the tumor site over other chemokines that have been associated with tumor development, including: CXCL12, CXCL10, CXCL8, CCL3, and CCL5. Subsequently, the immune response selectivity mounts an Ab-based response to CCL2. These Abs are neutralizing Abs. These findings hold diagnostic and therapeutic implications. The current diagnosis of prostate cancer is based on prostate-specific Ag measurements that do not distinguish benign hypertrophy from malignancy. We show in this study that development of anti-CCL2 Abs is selective to the malignant stage. From a clinically oriented perspective, we show, in an experimental model of the disease, that DNA-based amplification of this response suppresses disease, which has implications for a novel way of therapy in humans.


Asunto(s)
Quimiocina CCL2/análisis , Quimiocina CCL2/inmunología , Tolerancia Inmunológica , Neoplasias de la Próstata/inmunología , Anciano , Anciano de 80 o más Años , Animales , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Autoanticuerpos/biosíntesis , Autoanticuerpos/inmunología , Quimiocina CCL2/genética , Quimiocinas/análisis , ADN de Neoplasias/administración & dosificación , ADN de Neoplasias/inmunología , ADN de Neoplasias/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vacunas de ADN/administración & dosificación , Vacunas de ADN/farmacología
12.
Am J Pathol ; 176(6): 2764-75, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20382706

RESUMEN

The current study identifies within the Th1 subtype two distinct CD4(+) populations: those capable of transferring inflammatory autoimmunity and others that regulate its development by suppressing Th17 in an interferon (IFN)-gamma-dependent manner. These CD4(+)IFN-gamma(high)IL-4(low)IL-10(low)TGF-beta(low)FOXp3(-) cells in fact function as antigen-specific regulatory cells that restrain the development of autoimmunity by increasing the threshold of Th17 activation. We show that development of autoimmune conditions within the central nervous system is dependent on the Fas ligand-mediated apoptosis of these regulatory cells at early stages of disease. We also show that not only is the function of these cells IFN-gamma dependent but also that stable over expression of IFN-gamma in encephalitogenic CD4(+) T cells redirects their biological function to become antigen-specific regulatory cells. This may also explain, in part, the pleiotropic role of IFN-gamma in the regulation of autoimmunity, as previously observed by others.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Factores de Transcripción Forkhead/inmunología , Interferón gamma/inmunología , Interleucina-17/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Apoptosis/inmunología , Separación Celular , Proteína Ligando Fas/inmunología , Femenino , Citometría de Flujo , Humanos , Interferón gamma/genética , Ratones , Ratones Endogámicos C57BL
13.
J Immunol ; 182(12): 8104-9, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19494336

RESUMEN

We have recently demonstrated that patients suffering from chronic autoimmune diseases develop an autoantibody response against key mediators that participate in the initiation and progression of these diseases. In this paper, we show that patients with type 1 diabetes mellitus (T1DM), but not those suffering from several other inflammatory autoimmune diseases, display a selective autoantibody titer to a single CC chemokine named CCL3. From the diagnostic point we show that this response could be used as a biomarker for diagnosis of T1DM, a disease that is currently diagnosed by autoantibodies to competitive anti-insulin Abs, islet cell Abs, and glutamic acid decarboxylase Abs. We show that our currently suggested biomarker is more reliable than each of the above alone, including diagnosis of T1DM at its preclinical stage, and could therefore be used as a novel way for diagnosis of T1DM. These Abs were found to be neutralizing Abs. It is possible, though hard to prove, that these Abs participate in the natural regulation of the human disease. Hence, it has previously been shown by others that selective neutralization of CCL3 suppresses T1DM in NOD mice. Theses results together with ours suggest CCL3 as a preferential target for therapy of T1DM.


Asunto(s)
Formación de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Quimiocina CCL3/sangre , Quimiocina CCL3/inmunología , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/inmunología , Adolescente , Adulto , Especificidad de Anticuerpos , Biomarcadores/sangre , Línea Celular , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Humanos , Lactante
14.
J Immunol ; 183(1): 732-9, 2009 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-19535619

RESUMEN

CCL2 is a key CC chemokine that has been implicated in a variety of inflammatory autoimmune diseases and in tumor progression and it is therefore an important target for therapeutic intervention in these diseases. Soluble receptor-based therapy is a known approach for neutralizing the in vivo functions of soluble mediators. Owing to the complexity of seven-transmembrane G protein-coupled receptors, efforts to generate neutralizing soluble chemokine receptors have so far failed. We developed a strategy that is based on the generation of short recombinant proteins encoding different segments of a G protein-coupled receptor, and tested the ability of each of them to bind and neutralize its target chemokine. We show that a fusion protein comprised of as few as 20 aa of the third extracellular (E3) domain of the CCL2 receptor, stabilized by the IgG H chain Fc domain (E3-IgG or BL-2030), selectively binds CCL2 and CCL16 and effectively neutralizes their biological activities. More importantly, E3-IgG (BL-2030) could effectively suppress the in vivo biological activity of CCL2, attenuating ongoing experimental autoimmune encephalomyelitis, as well as the development of human prostate tumor in SCID mice.


Asunto(s)
Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/fisiología , Receptores CCR2/fisiología , Proteínas Recombinantes de Fusión/fisiología , Animales , Línea Celular , Línea Celular Tumoral , Inhibición de Migración Celular/inmunología , Proliferación Celular , Quimiocina CCL2/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Unión Proteica/inmunología , Estructura Terciaria de Proteína , Receptores CCR2/metabolismo , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/metabolismo
15.
Cancers (Basel) ; 13(24)2021 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-34944943

RESUMEN

Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with "cold tumors" that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (Tregs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of Tregs that are CCR8+ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity.

16.
Cell Stem Cell ; 28(7): 1248-1261.e8, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33984282

RESUMEN

The accessibility and transparency of the cornea permit robust stem cell labeling and in vivo cell fate mapping. Limbal epithelial stem cells (LSCs) that renew the cornea are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. Here, we combined single-cell RNA sequencing and advanced quantitative lineage tracing for in-depth analysis of the murine limbal epithelium. These analysis revealed the co-existence of two LSC populations localized in separate and well-defined sub-compartments, termed the "outer" and "inner" limbus. The primitive population of quiescent outer LSCs participates in wound healing and boundary formation, and these cells are regulated by T cells, which serve as a niche. In contrast, the inner peri-corneal limbus hosts active LSCs that maintain corneal epithelial homeostasis. Quantitative analyses suggest that LSC populations are abundant, following stochastic rules and neutral drift dynamics. Together these results demonstrate that discrete LSC populations mediate corneal homeostasis and regeneration.


Asunto(s)
Limbo de la Córnea , Células Madre , Animales , Córnea , Homeostasis , Ratones , Cicatrización de Heridas
17.
Front Immunol ; 11: 557586, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33193327

RESUMEN

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells. Under normal conditions, they differentiate into macrophages, dendritic cells, and granulocytes. Under pathological conditions, such as chronic inflammation, or cancer, they tend to maintain their immature state as immature myeloid cells that, within the tumor microenvironment, become suppressor cells and assist tumor escape from immune eradication. MDSC are comprised of two major subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Monocytic myeloid cells give rise to monocytic cells, whereas PMN-MDSC share similarities with neutrophils. Based on their biological activities, a two-stage model that includes the mobilization of the periphery as myeloid cells and their activation within the tumor microenvironment converting them into suppressor cells was previously suggested by D. Gabrilovich. From the migratory viewpoint, we are suggesting a more complex setup. It starts with crosstalk between the tumor site and the hematopoietic stem and progenitor cells (HSPCs) at the bone marrow (BM) and secondary lymphatic organs, resulting in rapid myelopoiesis followed by mobilization to the blood. Although myelopoiesis is coordinated by several cytokines and transcription factors, mobilization is selectively directed by chemokine receptors and may differ between M-MDSC and PMN-MDSC. These myeloid cells may then undergo further expansion at these secondary lymphatic organs and then home to the tumor site. Finally, selective homing of T cell subsets has been associated with retention at the target organs directed by adhesion molecules or chemokine receptors. The possible relevance to myeloid cells is still speculative but is discussed.


Asunto(s)
Diferenciación Celular , Movimiento Celular , Células Supresoras de Origen Mieloide/citología , Células Supresoras de Origen Mieloide/fisiología , Animales , Biomarcadores , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Quimiocinas/metabolismo , Humanos , Inmunomodulación , Inmunofenotipificación , Procesamiento Proteico-Postraduccional , Receptores CCR2/metabolismo , Receptores CCR5/metabolismo , Receptores de Quimiocina/metabolismo , Transducción de Señal
18.
Front Immunol ; 11: 976, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32547545

RESUMEN

CXCR3 is a chemokine receptor with three ligands; CXCL9, CXCL10, and CXCL11. CXCL11 binds CXCR3 with a higher affinity than the other ligands leading to receptor internalization. Long ago we reported that one of these chemokines, CXCL10, not only attracts CXCR3+ CD4+ and CD8+ effector T cells to sites of inflammation, but also direct their polarization into highly potent effector T cells. Later we showed that CXCL11 directs the linage development of T-regulatory-1 cells (Tr1). We also observed that CXCL11 and CXCL10 induce different signaling cascades via CXCR3. Collectively this suggests that CXCR3 ligands differentially regulate the biological function of T cells via biased signaling. It is generally accepted that tumor cells evolved to express several chemokine receptors and secrete their ligands. Vast majority of these chemokines support tumor growth by different mechanisms that are discussed. We suggest that CXCL10 and possibly CXCL9 differ from other chemokines by their ability to restrain tumor growth and enhance anti-tumor immunity. Along with this an accumulating number of studies showed in various human cancers a clear association between poor prognosis and low expression of CXCL10 at tumor sites, and vice versa. Finally, we discuss the possibility that CXCL9 and CXCL10 may differ in their biological function via biased signaling and its possible relevance to cancer immunotherapy. The current mini review focuses on exploring the role of CXCR3 ligands in directing the biological properties of CD4+ and CD8+ T cells in the context of cancer and autoimmunity. We believe that the combined role of these chemokines in attracting T cells and also directing their biological properties makes them key drivers of immune function.


Asunto(s)
Autoinmunidad , Linfocitos T CD4-Positivos/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/metabolismo , Quimiotaxis de Leucocito , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/metabolismo , Receptores CXCR3/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Humanos , Tolerancia Inmunológica , Ligandos , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Transducción de Señal , Microambiente Tumoral
20.
Front Immunol ; 9: 623, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29651292

RESUMEN

We have previously shown that predominant expression of key inflammatory cytokines and chemokines at autoimmune sites or tumor sites induces loss of B cells tolerance, resulting in autoantibody production against the dominant cytokine/chemokine that is largely expressed at these sites. These autoantibodies are high-affinity neutralizing antibodies. Based on animal models studies, we suggested that they participate in the regulation of cancer and autoimmunity, albeit at the level of their production cannot entirely prevent the development and progression of these diseases. We have, therefore, named this selective breakdown of tolerance as "Beneficial Autoimmunity." Despite its beneficial outcome, this process is likely to be stochastic and not directed by a deterministic mechanism, and is likely to be associated with the dominant expression of these inflammatory mediators at sites that are partially immune privileged. A recent study conducted on autoimmune regulator-deficient patients reported that in human this type of breakdown of B cell tolerance is T cell dependent. This explains, in part, why the response is highly restricted, and includes high-affinity antibodies. The current mini-review explores this subject from different complementary perspectives. It also discusses three optional translational aspects: amplification of autoantibody production as a therapeutic approach, development of autoantibody based diagnostic tools, and the use of B cells from donors that produce these autoantibodies for the development of high-affinity human monoclonal antibodies.


Asunto(s)
Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/inmunología , Linfocitos B/fisiología , Neoplasias/inmunología , Linfocitos T/inmunología , Animales , Afinidad de Anticuerpos , Autoinmunidad , Quimiocinas/metabolismo , Humanos , Tolerancia Inmunológica , Pruebas Inmunológicas
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