RESUMEN
Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.
Asunto(s)
Carcinoma , Inmunoglobulina A , Humanos , Inmunoglobulina A/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Citoplasma/metabolismoRESUMEN
The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4CreSatb1f/f mice enriched for antigen-specific Tfh cells, and TGF-ß-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1-/- CD4+ T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4CreSatb1f/f mice accumulated tumor antigen-specific, LIGHT+CXCL13+IL-21+ Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4+ T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4+ T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-ß-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors.
Asunto(s)
Centro Germinal/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Estructuras Linfoides Terciarias/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Diferenciación Celular , Regulación de la Expresión Génica , Silenciador del Gen , Genotipo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
Asunto(s)
Antígenos de Neoplasias/inmunología , Inmunoglobulina A/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Linfocitos T Citotóxicos/inmunología , Transcitosis , Especificidad de Anticuerpos , Antígenos CD/inmunología , Línea Celular , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Ováricas/prevención & control , Receptores Fc/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Transcitosis/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors.
Asunto(s)
Linfocitos B , Neoplasias , Linfocitos T , Estructuras Linfoides Terciarias , Animales , Humanos , Ratones , Inmunidad Adaptativa/inmunología , Linfocitos B/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/inmunología , Estructuras Linfoides Terciarias/inmunologíaRESUMEN
Despite the importance of programmed cell death-1 (PD-1) in inhibiting T cell effector activity, the mechanisms regulating its expression remain poorly defined. We found that the chromatin organizer special AT-rich sequence-binding protein-1 (Satb1) restrains PD-1 expression induced upon T cell activation by recruiting a nucleosome remodeling deacetylase (NuRD) complex to Pdcd1 regulatory regions. Satb1 deficienct T cells exhibited a 40-fold increase in PD-1 expression. Tumor-derived transforming growth factor ß (Tgf-ß) decreased Satb1 expression through binding of Smad proteins to the Satb1 promoter. Smad proteins also competed with the Satb1-NuRD complex for binding to Pdcd1 enhancers, releasing Pdcd1 expression from Satb1-mediated repression, Satb1-deficient tumor-reactive T cells lost effector activity more rapidly than wild-type lymphocytes at tumor beds expressing PD-1 ligand (CD274), and these differences were abrogated by sustained CD274 blockade. Our findings suggest that Satb1 functions to prevent premature T cell exhaustion by regulating Pdcd1 expression upon T cell activation. Dysregulation of this pathway in tumor-infiltrating T cells results in diminished anti-tumor immunity.
Asunto(s)
Represión Epigenética/inmunología , Regulación de la Expresión Génica/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de Unión a la Región de Fijación a la Matriz/biosíntesis , Receptor de Muerte Celular Programada 1/biosíntesis , Animales , Ensayo de Immunospot Ligado a Enzimas , Humanos , Inmunoprecipitación , Activación de Linfocitos/inmunología , Proteínas de Unión a la Región de Fijación a la Matriz/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/metabolismoRESUMEN
Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.
Asunto(s)
Endorribonucleasas/metabolismo , Mitocondrias/metabolismo , Neoplasias Ováricas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Proteína 1 de Unión a la X-Box/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animales , Ascitis/metabolismo , Respiración de la Célula , Progresión de la Enfermedad , Estrés del Retículo Endoplásmico , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Glutamina/metabolismo , Glicosilación , Humanos , Interferón gamma/biosíntesis , Interferón gamma/genética , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Neoplasias Ováricas/patología , Transducción de Señal , Tasa de Supervivencia , Linfocitos T/metabolismo , Escape del Tumor/inmunología , Respuesta de Proteína Desplegada , Proteína 1 de Unión a la X-Box/biosíntesis , Proteína 1 de Unión a la X-Box/deficienciaRESUMEN
Solid cancers progress from primordial lesions through complex interactions between tumor-promoting and anti-tumor immune cell types, ultimately leading to the orchestration of humoral and T cell adaptive immune responses, albeit in an immunosuppressive environment. B cells infiltrating most established tumors have been associated with a dual role: Some studies have associated antibodies produced by tumor-associated B cells with the promotion of regulatory activities on myeloid cells, and also with direct immunosuppression through the production of IL-10, IL-35 or TGF-ß. In contrast, recent studies in multiple human malignancies identify B cell responses with delayed malignant progression and coordinated T cell protective responses. This includes the elusive role of Tertiary Lymphoid Structures identified in many human tumors, where the function of B cells remains unknown. Here, we discuss emerging data on the dual role of B cell responses in the pathophysiology of human cancer, providing a perspective on future directions and possible novel interventions to restore the coordinated action of both branches of the adaptive immune response, with the goal of maximizing immunotherapeutic effectiveness.
Asunto(s)
Linfocitos B/inmunología , Inmunidad Humoral , Neoplasias/etiología , Animales , Linfocitos B/metabolismo , Biomarcadores , Citocinas/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Inmunomodulación , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Microambiente Tumoral/inmunologíaRESUMEN
Radiation therapy (RT) can prime and boost systemic anti-tumor effects via STING activation, resulting in enhanced tumor antigen presentation and antigen recognition by T cells. It is increasingly recognized that optimal anti-tumor immune responses benefit from coordinated cellular (T cell) and humoral (B cell) responses. However, the nature and functional relevance of the RT-induced immune response are controversial, beyond STING signaling, and agonistic interventions are lacking. Here, we show that B and CD4+ T cell accumulation at tumor beds in response to RT precedes the arrival of CD8+ T cells, and both cell types are absolutely required for abrogated tumor growth in non-irradiated tumors. Further, RT induces increased expression of 4-1BB (CD137) in both T and B cells; both in preclinical models and in a cohort of patients with small cell lung cancer treated with thoracic RT. Accordingly, the combination of RT and anti-41BB therapy leads to increased immune cell infiltration in the tumor microenvironment and significant abscopal effects. Thus, 4-1BB therapy enhances radiation-induced tumor-specific immune responses via coordinated B and T cell responses, thereby preventing malignant progression at unirradiated tumor sites. These findings provide a rationale for combining RT and 4-1bb therapy in future clinical trials.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Neoplasias/radioterapia , Inmunoterapia , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Activación de Linfocitos , Microambiente TumoralRESUMEN
OBJECTIVE: To demonstrate that shared antibody responses in endometriosis and endometriosis-associated ovarian cancer spontaneously antagonize malignant progression and can be leveraged to develop future immunotherapies. METHODS: B cells from cyopreserved clear cell ovarian carcinoma (CCC, n = 2), endometrioid ovarian carcinoma (EC, n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening arrays containing most of the human proteome. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. We focused on antibodies targeting tumor-promoting syndecan binding protein (SDCBP) to demonstrate anti-tumor activity. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer and endometriosis cell lines and tumor samples. Recombinant IgG4 was generated using the variable heavy and light chains of dominant B cell receptors (BCRs) reacting against the extracellular domain of SDCBP, and used in in vivo studies in human CCC- and high-grade serous ovarian carcinoma (HGSOC)-bearing immunodeficient mice. RESULTS: Nine accessible proteins detected by both IgA and IgG were identified in all samples - including SDCBP, which is expressed in ovarian carcinomas of multiple histologies. Administration of α-SDCBP IgG4 in OVCAR3 (HGSOC), TOV21G and RMG-I (CCC) tumor-bearing mice significantly decreased tumor volume compared to control irrelevant IgG4. CONCLUSIONS: Spontaneous antibody responses exert suboptimal but measurable immune pressure against malignant progression in ovarian carcinomas. Using tumor-derived antibodies for developing novel immunotherapeutics warrants further investigation.
Asunto(s)
Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Endometriosis , Neoplasias Ováricas , Humanos , Femenino , Animales , Ratones , Neoplasias Ováricas/patología , Apoptosis , Formación de Anticuerpos , Línea Celular Tumoral , Carcinoma Epitelial de Ovario , Carcinoma Endometrioide/patología , Inmunoglobulina A/metabolismo , Adenocarcinoma de Células Claras/patología , Sinteninas/metabolismoRESUMEN
Immuno-oncology has traditionally focused on conventional MHC-restricted αß T cells. Yet, unconventional γδ T cells, which kill tumor cells in an MHC-unrestricted manner, display characteristics of effector activity and stemness without exhaustion and are nearly universally observed in human gynecologic malignancies, correlating with improved outcomes. These cells do not have a clear counterpart in mice but are also found in the healthy female reproductive tract. Interventions that modulate their in vivo activity, or cellular therapies utilizing γδ T cells as an allogeneic, "off-the-shelf" platform (e.g., for chimeric antigen receptor expression) hold significant potential against challenging tumors like ovarian cancer, which has been stubbornly resistant to the immune checkpoint inhibitors that change the landscape of other human tumors. Here, we discuss recent discoveries on the specific populations of γδ T cells that infiltrate human gynecologic cancers, their anti-tumor activity, and the prospect of redirecting their effector function against tumor cells to develop a new generation of immunotherapies that extends beyond the traditional αß T cell-centric view of the field.
RESUMEN
Healthy cells exhibit an asymmetric plasma membrane with phosphatidylserine (PS) located on the cytoplasmic leaflet of the plasma membrane bilayer. Annexin A5-FITC, a PS binding protein, is commonly used to evaluate apoptosis in flow cytometry. PS exposed by apoptotic cells serves as a major 'eat-me' signal for phagocytes. Although exposition of PS has been observed after alternative stimuli, no clearance of viable, PS exposing cells has been detected. Thus, besides PS exposure, membranes of viable and apoptotic cells might exhibit specific characteristics. Here, we show that Annexin A5 binds in a cooperative manner to different types of dead cells. Shrunken apoptotic cells thereby showed the highest Hill coefficient values. Contrarily, parafomaldehyde fixation of apoptotic cells completely abrogates the cooperativity effect seen with dead and dying cells. We tend to speculate that the cooperative binding of Annexin A5 to the membranes of apoptotic cells reflects higher fluidity of the exposed membranes facilitating PS clustering.
Asunto(s)
Anexina A5/metabolismo , Apoptosis , Membrana Celular/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Fosfatidilserinas/metabolismo , Células Cultivadas , Citometría de Flujo , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Unión ProteicaRESUMEN
Apoptotic cell death and the clearance of dying cells play an important and physiological role in embryonic development and normal tissue turnover. In contrast to necrosis, apoptosis proceeds in an anti-inflammatory manner. It is orchestrated by the timed release and/or exposure of so-called 'find-me', 'eat me' and 'tolerate me' signals. Mononuclear phagocytes are attracted by various 'find-me' signals, including proteins, nucleotides, and phospholipids released by the dying cell, whereas the involvement of granulocytes is prevented via 'stay away' signals. The exposure of anionic phospholipids like phosphatidylserine (PS) by apoptotic cells on the outer leaflet of the plasma membrane is one of the main 'eat me' signals. PS is recognized by a number of innate receptors as well as by soluble bridging molecules on the surface of phagocytes. Importantly, phagocytes are able to discriminate between viable and apoptotic cells both exposing PS. Due to cytoskeleton remodeling PS has a higher lateral mobility on the surfaces of apoptotic cells thereby promoting receptor clustering on the phagocyte. PS not only plays an important role in the engulfment process, but also acts as 'tolerate me' signal inducing the release of anti-inflammatory cytokines by phagocytes. An efficient and fast clearance of apoptotic cells is required to prevent secondary necrosis and leakage of intracellular danger signals into the surrounding tissue. Failure or prolongation of the clearance process leads to the release of intracellular antigens into the periphery provoking inflammation and development of systemic inflammatory autoimmune disease like systemic lupus erythematosus. Here we review the current findings concerning apoptosis-inducing pathways, important players of apoptotic cell recognition and clearance as well as the role of membrane remodeling in the engulfment of apoptotic cells by phagocytes.
Asunto(s)
Apoptosis , Fosfatidilserinas/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Humanos , Fagocitos/citología , Fagocitos/inmunología , Fagocitos/metabolismo , Fagocitosis , Fosfatidilserinas/inmunología , Transducción de SeñalRESUMEN
The reaction of hydrogen sulfide (H2S) with peroxynitrite (a key mediator in numerous pathological states) was studied in vitro and in different cellular models. The results show that H2S can scavenge peroxynitrite with a corresponding second order rate constant of 3.3 ± 0.4 × 10³ M⻹·s⻹ at 23°C (8 ± 2 × 10³ M⻹·s⻹ at 37°C). Activation parameters for the reaction (ΔH, ΔS and ΔV) revealed that the mechanism is rather associative than multi-step free-radical as expected for other thiols. This is in agreement with a primary formation of a new reaction product characterized by spectral and computational studies as HSNO2 (thionitrate), predominantly present as sulfinyl nitrite, HS(O)NO. This is the first time a thionitrate has been shown to be generated under biologically relevant conditions. The potential of HS(O)NO to serve as a NO donor in a pH-dependent manner and its ability to release NO inside the cells has been demonstrated. Thus sulfide modulates the chemistry and biological effects of peroxynitrite by its scavenging and formation of a new chemical entity (HSNO2) with the potential to release NO, suppressing the pro-apoptotic, oxidative and nitrative properties of peroxynitrite. Physiological concentrations of H2S abrogated peroxynitrite-induced cell damage as demonstrated by the: (i) inhibition of apoptosis and necrosis caused by peroxynitrite; (ii) prevention of protein nitration; and (iii) inhibition of PARP-1 [poly(ADP-ribose) polymerase 1] activation in cellular models, implying that a major part of the cytoprotective effects of hydrogen sulfide may be mediated by modulation of peroxynitrite chemistry, in particular under inflammatory conditions.
Asunto(s)
Sulfuro de Hidrógeno/metabolismo , Donantes de Óxido Nítrico/síntesis química , Nitritos/síntesis química , Ácido Peroxinitroso/metabolismo , Apoptosis/efectos de los fármacos , Células HeLa , Humanos , Sulfuro de Hidrógeno/química , Células Jurkat , Cinética , Ácido Peroxinitroso/química , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) PolimerasasRESUMEN
Magnetic drug targeting (MDT) improves the integrity of healthy tissues and cells during treatment with cytotoxic drugs. An anticancer drug is bound to superparamagnetic iron oxide nanoparticles (SPION), injected into the vascular supply of the tumor and directed into the tumor by means of an external magnetic field. In this study, we investigated the impact of SPION, mitoxantrone (MTO) and SPIONMTO on cell viability in vitro and the nonspecific uptake of MTO into circulating leukocytes in vivo. MDT was compared with conventional chemotherapy. MTO uptake and the impact on cell viability were assessed by flow cytometry in a Jurkat cell culture. In order to analyze MTO loading of circulating leukocytes in vivo, we treated tumor-bearing rabbits with MDT and conventional chemotherapy. In vitro experiments showed a dose-dependent MTO uptake and reduction in the viability and proliferation of Jurkat cells. MTO and SPIONMTO showed similar cytotoxic activity. Non-loaded SPION did not have any effect on cell viability in the concentrations tested. Compared with systemic administration in vivo, MDT employing SPIONMTO significantly decreased the chemotherapeutic load in circulating leukocytes. We demonstrated that MDT spares the immune system in comparison with conventional chemotherapy.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Citotoxinas , Sistemas de Liberación de Medicamentos/métodos , Leucocitos/metabolismo , Campos Magnéticos , Nanopartículas de Magnetita/química , Neoplasias Experimentales , Animales , Citotoxinas/química , Citotoxinas/farmacología , Femenino , Humanos , Células Jurkat , Leucocitos/patología , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , ConejosRESUMEN
The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26-/CD7- lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26-/CD7- lymphocytes, we show that tumor cells in Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.
Asunto(s)
Linfoma Cutáneo de Células T , Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Síndrome de Sézary/genética , Síndrome de Sézary/patología , Dipeptidil Peptidasa 4 , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Micosis Fungoide/genética , Micosis Fungoide/patología , Linfoma Cutáneo de Células T/genética , Receptores de Antígenos de Linfocitos TRESUMEN
Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies. SIGNIFICANCE: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766.
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Neoplasias Endometriales , Receptores de Inmunoglobulina Polimérica , Linfocitos B/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Inmunidad Humoral , Inmunoglobulina A/metabolismo , Receptores de Inmunoglobulina Polimérica/genética , Receptores de Inmunoglobulina Polimérica/metabolismo , Microambiente TumoralRESUMEN
Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.
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Neoplasias Pulmonares , Neoplasias Glandulares y Epiteliales , Neoplasias Ováricas , Receptores Odorantes , Femenino , Humanos , Línea Celular Tumoral , Inmunoterapia Adoptiva , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Receptores Odorantes/metabolismo , Linfocitos TRESUMEN
Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1low) tissue-resident T cells (TRMstem cells), but not recirculating TCF1+ T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on â¼13% of CD8+ tumor-infiltrating T cells (â¼3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.
Asunto(s)
Memoria Inmunológica , Neoplasias Ováricas , Linfocitos T CD8-positivos , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Células T de MemoriaRESUMEN
Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Metiltransferasas/antagonistas & inhibidores , Proteínas de Neoplasias , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Humanos , Metiltransferasas/metabolismo , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αß and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αß T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αß T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αß and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.