RESUMEN
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.
Asunto(s)
Adenocarcinoma del Pulmón/inmunología , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Neoplasias Pulmonares/inmunología , Células Madre/inmunología , Secuencia de Aminoácidos , Animales , Antígeno CTLA-4/metabolismo , Epítopos , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/patología , Ratones , Péptidos/química , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , RNA-Seq , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CCR6/metabolismo , Análisis de la Célula Individual , VacunaciónRESUMEN
CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa/inmunología , Memoria Inmunológica/inmunología , Vigilancia Inmunológica/inmunología , Membrana Mucosa/inmunología , Animales , Femenino , Microscopía Intravital , Ratones , Membrana Mucosa/citología , Piel/inmunologíaRESUMEN
In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity.
Asunto(s)
Adenocarcinoma del Pulmón/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Neoplasias Pulmonares/inmunología , Ganglios Linfáticos/inmunología , Factor 1 de Transcripción de Linfocitos T/inmunología , Animales , Ratones , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces; thus, infection detection rates depend on memory cell number and distribution. Population analyses rely on cell isolation from whole organs, and interpretation is predicated on presumptions of near complete cell recovery. Paradigmatically, memory is parsed into central, effector, and resident subsets, ostensibly defined by immunosurveillance patterns but in practice identified by phenotypic markers. Because isolation methods ultimately inform models of memory T cell differentiation, protection, and vaccine translation, we tested their validity via parabiosis and quantitative immunofluorescence microscopy of a mouse memory CD8 T cell population. We report three major findings: lymphocyte isolation fails to recover most cells and biases against certain subsets, residents greatly outnumber recirculating cells within non-lymphoid tissues, and memory subset homing to inflammation does not conform to previously hypothesized migration patterns. These results indicate that most host cells are surveyed for reinfection by segregated residents rather than by recirculating cells that migrate throughout the blood and body.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/fisiología , Monitorización Inmunológica , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD8-positivos/inmunología , Movimiento Celular , Inflamación/inmunología , Lectinas Tipo C/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS, BRAF, and ALK mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Animales , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Organoides , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex class I (MHC-I) molecules1-5. Current approaches to profiling of MHC-I-associated peptides, collectively known as the immunopeptidome, are limited to in vitro investigation or bulk tumour lysates, which limits our understanding of cancer-specific patterns of antigen presentation in vivo6. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (H2-K1) and targeted this allele to the KrasLSL-G12D/+Trp53fl/fl mouse model (KP/KbStrep)7. This approach enabled us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma and from lung adenocarcinoma (LUAD) in vivo. In addition, we profiled the LUAD immunopeptidome from the alveolar type 2 cell of origin up to late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is probably driven by post-translational mechanisms. Vaccination with peptides presented by LUAD in vivo induced CD8+ T cell responses in naive mice and tumour-bearing mice. Many peptides specific to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, which prompts the reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance8. Beyond cancer, the KbStrep allele is compatible with other Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease and autoimmunity.
Asunto(s)
Antígenos de Neoplasias , Péptidos , Proteómica , Células Epiteliales Alveolares/inmunología , Animales , Presentación de Antígeno , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/química , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Neoplasias Pulmonares/química , Neoplasias Pulmonares/inmunología , Ratones , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/inmunología , Péptidos/análisis , Péptidos/química , Péptidos/inmunología , ARN MensajeroRESUMEN
Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T (Trm) cells remain parked in nonlymphoid tissues and often stably express CD69. We recently identified Trm cells within SLO, but the origin and phenotype of these cells remains unclear. Using parabiosis of "dirty" mice, we found that CD69 expression is insufficient to infer stable residence of SLO Trm cells. Restimulation of nonlymphoid memory CD8+ T cells within the skin or mucosa resulted in a substantial increase in bona fide Trm cells specifically within draining lymph nodes. SLO Trm cells derived from emigrants from nonlymphoid tissues and shared some transcriptional and phenotypic signatures associated with nonlymphoid Trm cells. These data indicate that nonlymphoid cells can give rise to SLO Trm cells and suggest vaccination strategies by which memory CD8+ T cell immunosurveillance can be regionalized to specific lymph nodes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Ganglios Linfáticos/inmunología , Animales , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Femenino , Lectinas Tipo C/análisis , Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.
Asunto(s)
Receptor Cross-Talk , Receptores de Antígenos de Linfocitos T/agonistas , Linfocitos T Reguladores/inmunología , Timo/inmunología , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Antígenos CD28/genética , Antígenos CD28/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Cross-Talk/inmunología , Receptores OX40/genética , Receptores OX40/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genéticaRESUMEN
Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer progression. Moreover, leukocyte trafficking depended on the integrins CD11a/CD49d, and CD11a/CD49d blockade led to significant tumor burden reduction in mice. Importantly, preventing circulating Treg recruitment through depletion or sequestration in lymph nodes was sufficient to decrease tumor burden, indicating that Treg migration was crucial for suppressing antitumor immunity. These findings underscore the dynamic nature of the immune compartment within mouse lung tumors and demonstrate the relevance of a temporal map of leukocyte recruitment into tumors, thereby advancing our understanding of leukocyte migration in the context of tumor development.
RESUMEN
CD8(+) T cells eliminate intracellular infections through two contact-dependent effector functions: cytolysis and secretion of antiviral cytokines. Here we identify the following additional function for memory CD8(+) T cells that persist at front-line sites of microbial exposure: to serve as local sensors of previously encountered antigens that precipitate innate-like alarm signals and draw circulating memory CD8(+) T cells into the tissue. When memory CD8(+) T cells residing in the female mouse reproductive tract encountered cognate antigen, they expressed interferon-γ (IFN-γ), potentiated robust local expression of inflammatory chemokines and induced rapid recruitment of circulating memory CD8(+) T cells. Anamnestic responses in front-line tissues are thus an integrated collaboration between front-line and circulating populations of memory CD8(+) T cells, and vaccines should establish both populations to maximize rapid responses.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos Virales/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Femenino , Genitales Femeninos/inmunología , Interacciones Huésped-Patógeno , Interferón gamma/genética , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Quimera por TrasplanteRESUMEN
Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2-dependent resident Th2 memory cells as drivers of lung allergic responses.
Asunto(s)
Asma/inmunología , Memoria Inmunológica/inmunología , Interleucina-2/inmunología , Pulmón/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Diferenciación Celular/inmunología , Separación Celular , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pyroglyphidae/inmunologíaRESUMEN
Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating. They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance. Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells. In this review, we will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population.
Asunto(s)
Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Diferenciación Celular , Movimiento Celular , Humanos , InmunidadRESUMEN
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Carga Tumoral/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Antígeno Ki-67/inmunología , Antígeno Ki-67/metabolismo , Masculino , Melanoma/irrigación sanguínea , Melanoma/patología , Estadificación de Neoplasias , Fenotipo , Resultado del TratamientoRESUMEN
Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, loss of p107 results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130 Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.
Asunto(s)
Edición Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Apoptosis/genética , Sistemas CRISPR-Cas/genética , Línea Celular , Proliferación Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estudios de Factibilidad , Humanos , Mutación con Pérdida de Función , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Estadificación de Neoplasias , Proteína p107 Similar a la del Retinoblastoma/genética , Proteína p130 Similar a la del Retinoblastoma/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carga Tumoral/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
Asunto(s)
Inmunoterapia/métodos , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/uso terapéutico , Inyecciones Intralesiones , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Linfocitos B , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/inmunología , Humanos , Inmunidad Celular , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana , Interleucina-10 , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Proteínas Represoras/genética , Estaciones del Año , Piel , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Escualeno/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , VacunaciónRESUMEN
With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.
Asunto(s)
Neoplasias/tratamiento farmacológico , Neurociencias , Dolor en Cáncer/tratamiento farmacológico , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/etiología , Neoplasias/inmunología , Neoplasias/patología , Fenómenos Fisiológicos del Sistema Nervioso/efectos de los fármacos , Microambiente TumoralRESUMEN
Memory CD8+ T cell quantity and quality determine protective efficacy against reinfection. Heterologous prime boost vaccination minimizes contraction of anamnestic effectors and maximizes memory CD8+ T cell quantity but reportedly erodes proliferative potential and protective efficacy. This study exploited heterologous prime boost vaccination to discover parameters regulating effector CD8+ T cell contraction and memory differentiation. When abundant memory T cells were established, boosting induced only 5-8 cell divisions, unusually rapid memory T cell differentiation as measured by phenotype and mitochondrial bioenergetic function, long-lived survival of 50% of effector T cells, and preservation of proliferative potential. Conversely, boosting in situations of low memory CD8+ T cell frequencies induced many cell divisions, increased contraction of effector cells, and caused senescence, low mitochondrial membrane potential, and poorly protective memory. Thus, anamnestic memory T cell differentiation is flexible, and abundant quantity can be achieved while maximizing protective efficacy and preserving proliferative potential.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Inmunización Secundaria/métodos , Memoria Inmunológica/inmunología , Animales , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Supervivencia Celular/inmunología , Citometría de Flujo , Inmunofenotipificación , Ratones , Ratones Endogámicos C57BL , Mitocondrias/inmunología , Mitocondrias/metabolismo , Factores de TiempoRESUMEN
Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.
Asunto(s)
Crianza de Animales Domésticos/métodos , Animales de Laboratorio/inmunología , Animales Salvajes/inmunología , Ambiente , Sistema Inmunológico/inmunología , Inmunidad/inmunología , Modelos Animales , Adulto , Animales , Diferenciación Celular , Exposición a Riesgos Ambientales , Femenino , Humanos , Inmunidad Innata/inmunología , Memoria Inmunológica , Recién Nacido , Masculino , Ratones , Fenotipo , Organismos Libres de Patógenos Específicos , Linfocitos T/citología , Linfocitos T/inmunología , Virosis/inmunología , Virosis/virologíaRESUMEN
More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4+ T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4+ T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively (P = .019), and CD8+ T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively (P < .001). The leukoreduction system chamber's lymphocyte-extraction efficiency was â¼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4+ T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4+ and CD8+ effector memory, Th1, and regulatory T cell percentages, and stable naive CD8+ and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4+ and CD8+ T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful.
Asunto(s)
Donantes de Sangre/estadística & datos numéricos , Plaquetas/citología , Linfopenia/etiología , Plaquetoferesis/efectos adversos , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Pronóstico , Adulto JovenRESUMEN
IL-15 regulates central and effector memory CD8 T cell (TCM and TEM, respectively) homeostatic proliferation, maintenance, and longevity. Consequently, IL-15 availability hypothetically defines the carrying capacity for total memory CD8 T cells within the host. In conflict with this hypothesis, previous observations demonstrated that boosting generates preternaturally abundant TEM that increases the total quantity of memory CD8 T cells in mice. In this article, we provide a potential mechanistic explanation by reporting that boosted circulating TEM do not require IL-15 for maintenance. We also investigated tissue-resident memory CD8 T cells (TRM), which protect nonlymphoid tissues from reinfection. We observed up to a 50-fold increase in the total magnitude of TRM in mouse mucosal tissues after boosting, suggesting that the memory T cell capacity in tissues is flexible and that TRM may not be under the same homeostatic regulation as primary central memory CD8 T cells and TEM Further analysis identified distinct TRM populations that depended on IL-15 for homeostatic proliferation and survival, depended on IL-15 for homeostatic proliferation but not for survival, or did not depend on IL-15 for either process. These observations on the numerical regulation of T cell memory indicate that there may be significant heterogeneity among distinct TRM populations and also argue against the common perception that developing vaccines that confer protection by establishing abundant TEM and TRM will necessarily erode immunity to previously encountered pathogens as the result of competition for IL-15.