RESUMEN
NK cells orchestrate the tumor destruction and control metastasis in a coordinated way with other immune cells of the tumor microenvironment. However, NK cell infiltration in the tumor microenvironment is limited, and tumor cells have developed numerous mechanisms to escape NK cell attack. As a result, NK cells that have been able to infiltrate the tumors are exhausted, and metabolically and functionally impaired. Depending this impairment the prognostic and theranostic values of NK cells differ depending on the studies, the type of cancer, the stage of tumor and the nature of the tumor microenvironment. Extensive studies have been done to investigate different strategies to improve the NK cell function, and nowadays, a battery of therapeutic tools are being tested, with promising results.
Asunto(s)
Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Animales , Humanos , Vigilancia Inmunológica , Neoplasias/diagnóstico , Neoplasias/terapia , Pronóstico , Escape del Tumor , Microambiente TumoralRESUMEN
Toll-like receptors (TLRs) in the tumor microenvironment (TME) are expressed not only in innate and adaptive immune cells but also in stromal cells such as fibroblasts, endothelial cells (EC), and tumor cells. The role of TLR signaling in the TME is complex and controversial due to their wide expression within the TME. Moreover, TLR signaling may culminate in different outcomes depending on the type of tumor, the implicated TLR, the type of TLR ligands, and, most importantly, the main type of cell(s) that are targeted by TLR ligands. Understanding to what extent these complex TLR signals impact on tumor progression merits further investigation, as it can help improve existing anti-cancer treatments or unravel new ones. In most cases, TLR signaling in tumor cells and in immune cells is associated with pro-tumoral and anti-tumoral effects, respectively. A better understanding of the relationship between TLRs and the TME, especially in humans, is required to design better anti-cancer therapies, considering that most current TLR-involved treatments were disappointing in clinical trials.In this chapter, we will discuss the impact of TLR signaling on the hallmarks of cancer, by highlighting their effects in tumor, immune, and stromal cells within the TME. Furthermore, we will discuss how the understanding of the role of TLRs can pave the way to develop new anti-cancer treatments and even predict clinical outcome and chemotherapy efficacy.
Asunto(s)
Neoplasias/inmunología , Neoplasias/metabolismo , Receptores Toll-Like/metabolismo , Microambiente Tumoral , Humanos , Transducción de SeñalRESUMEN
Among the inflammatory myopathies, anti-tRNA-synthetase syndrome (ASyS) is a severe autoimmune condition characterized by extramuscular involvement, affecting especially the lungs. ASyS specific serological markers are anti-tRNA-synthetase autoantibodies, among which anti-histidyl-tRNA-synthetase is the most common. In the past decades, ASyS has been distinguished by unique histological features attributed to a specific pathogenesis. Research has highlighted the role of environmental factors and infections as possible triggers. Tissue modifications of histidyl-tRNA-synthetase (HisRS) expression might be responsible for the recruitment and activation of both innate and adaptive immune cells. HisRS not only acts through antigenic properties, but also through many others, including chemoattraction, innate pathway activation, and cytokine-like functions. Favored by a certain genetic background, this whole activation of immunity results in widespread and specific tissue damage and finally leads to visible heterogeneous symptoms characterizing the disease state. Understanding the pathogenesis of ASyS is essential to improving patient care by identifying biomarkers and designing new therapeutic strategies accordingly. Therefore, this review details the recent hypotheses concerning the dynamic of ASyS pathogenesis with the aim of enlightening the development of new therapeutic axes in the future.
Asunto(s)
Miositis/inmunología , Miositis/patología , Animales , Histidina-ARNt Ligasa/biosíntesis , Histidina-ARNt Ligasa/inmunología , Histidina-ARNt Ligasa/metabolismo , Humanos , Miositis/genéticaRESUMEN
RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. OBJECTIVES: To study the impact of COPD on the immune contexture of non-small cell lung cancer. METHODS: We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status. MEASUREMENTS AND MAIN RESULTS: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. CONCLUSIONS: COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Microambiente Tumoral/inmunología , Anciano , Análisis de Varianza , Biopsia con Aguja , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/patología , Estudios Retrospectivos , Medición de Riesgo , Análisis de SupervivenciaRESUMEN
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called "damage-associated molecular patterns," DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.
Asunto(s)
Crisis Blástica/inmunología , Crisis Blástica/patología , Calreticulina/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Alarminas/metabolismo , Linfocitos T CD8-positivos/inmunología , Muerte Celular , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Inmunidad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , Modelos de Riesgos Proporcionales , Células TH1/inmunología , Transcripción Genética , Resultado del TratamientoRESUMEN
Antisynthetase syndrome (aSS) is characterized by the association of interstitial lung disease and myositis with anti-tRNA synthetase autoantibodies. Immune mechanisms leading to aSS could be initiated in the lungs, but the role of NK cells has not yet been studied. Both extensive NK cell phenotype and functions were compared between 33 patients and 26 controls. Direct and redirected polyfunctionality assays (degranulation and intracellular production of TNF-α and IFN-γ) were performed spontaneously or after IL-12 plus IL-18 stimulation in the presence of K562 or P815 target cells, respectively. NK cells from inactive patients showed normal phenotype, whereas active aSS revealed a differentiated NK cell profile, as indicated by increased CD57 and Ig-like transcript 2 and an inability to produce IFN-γ (p = 0.002) compared with controls. Importantly, active aSS was more specifically associated with a significant NKp30 decrease (p = 0.009), although levels of mRNA and intracellular protein were similar in aSS and healthy controls. This NKp30 decrease was strongly correlated with reduced NK cell polyfunctionality in both direct and redirected killing assays with anti-NKp30 Abs (p = 0.009 and p = 0.03, respectively), confirming its important impact in aSS. Histological studies revealed massive infiltrations of NK cells inside the lungs of aSS patients (148 versus 11/mm(2)). Taken together, these data suggest that NK cells and NKp30 could play a role in aSS pathogenesis.
Asunto(s)
Células Asesinas Naturales/inmunología , Miositis/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/metabolismo , Adulto , Anciano , Antígenos CD57/genética , Femenino , Granzimas , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-12/sangre , Interleucina-12/inmunología , Interleucina-18/sangre , Interleucina-18/inmunología , Células K562 , Pulmón/inmunología , Pulmón/patología , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Persona de Mediana Edad , Miositis/fisiopatología , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Fenotipo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología , Adulto JovenRESUMEN
Type I IFNs are a family of cytokines with antiviral and immunomodulatory properties. Although the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. To specifically address the effects of type I IFNs on T regulatory cells (Tregs), we studied mixed bone marrow chimeras between wild-type and IFN-α/ß receptor (IFNAR) knockout (KO) mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. In these two models, IFNAR signaling promotes the development of the Treg lineage in the thymus and their survival in the periphery. IFNAR KO Tregs had a higher expression of the proapoptotic gene Bim and higher frequency of active caspase-positive cells. IFNAR KO Tregs from chimeric mice displayed a more naive phenotype, accompanied by lower levels of CD25 and phosphorylated STAT5. Therefore, in Tregs, IFNAR signaling may directly or indirectly affect phosphorylation of STAT5. In mixed chimeras with Scurfy fetal liver, Tregs derived from IFNAR KO bone marrow were unable to control T effector cell activation and tissue inflammation. Under stress conditions or in a competitive environment, IFNAR signaling may be required to maintain Treg homeostasis and function.
Asunto(s)
Receptor de Interferón alfa y beta/metabolismo , Transducción de Señal , Estrés Fisiológico , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Supervivencia Celular/genética , Quimera , Femenino , Técnicas de Inactivación de Genes , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interferón Tipo I/metabolismo , Interferón Tipo I/farmacología , Interleucina-2/metabolismo , Interleucina-2/farmacología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Masculino , Ratones , Ratones Noqueados , Fenotipo , Fosforilación/efectos de los fármacos , Poli I-C/farmacología , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Timo/inmunología , Timo/metabolismoRESUMEN
Three subpopulations of circulating monocytes have been described: CD14(2+)CD16(-) (classical monocytes [CM]), CD14(2+)CD16(+) (intermediate monocytes [IM]), and CD14(+)CD16(2+) (nonclassical monocytes [NCM]). We previously showed that obesity is associated with an increased proportion of IM and NCM. Our objective is to decipher the migratory and inflammatory functions of each monocyte subset in obesity-related low-grade inflammation. Twenty-six healthy, normal-weight and nondiabetic volunteers (C) and 40 obese nondiabetic (Ob) individuals were included in this study. We explored the gene expression profile of 18 inflammatory genes in each subset of C and Ob subjects and measured protein expression of the upregulated genes. We then tested their functional response to TLR signaling in both groups. We showed an increased expression of CX3CR1 in all monocyte subpopulations and of CCR2 and CCR5 in CM and IM in the Ob group. We found negative correlation between CCR2 and CX3CR1 expressions and high-density lipoprotein-cholesterol, whereas CCR5 expression was positively linked to obesity-related metabolic traits. Production of inflammatory proteins upon bacterial LPS and viral ssRNA stimulation was higher in CM and NCM of the Ob group compared with the C group. Our work highlights an enhanced inflammatory phenotype of monocytes with a higher response to TLR4 and TLR8 stimulations in obesity. Moreover, it suggests an increased migration capacity of CM and IM subpopulations.
Asunto(s)
Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Monocitos/inmunología , Adulto , Receptor 1 de Quimiocinas CX3C , Femenino , Proteínas Ligadas a GPI/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mediadores de Inflamación/inmunología , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Masculino , Monocitos/patología , Obesidad , Receptores CCR2/inmunología , Receptores CCR5/inmunología , Receptores de Quimiocina/inmunología , Receptores de IgG/inmunología , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/inmunologíaRESUMEN
RATIONALE: Tumor-infiltrating immune cells affect lung cancer outcome. However, the factors that influence the composition and function of the tumor immune environment remain poorly defined and need investigation, particularly in the era of immunotherapy. OBJECTIVES: To determine whether the tumoral immune environment is related to lung adenocarcinoma mutations. METHODS: This retrospective cohort included 316 consecutive patients with lung adenocarcinoma (225 men; 258 smokers) studied from 2001 to 2005 in a single center. We investigated the association of densities of intratumoral mature dendritic cells (mDCs), CD8+ T cells, neutrophils, and macrophages with clinical and pathological variables and tumor cell mutation profiles obtained by next-generation sequencing. MEASUREMENTS AND MAIN RESULTS: In 282 tumors, we found 460 mutations, mainly in TP53 (59%), KRAS (40%), STK11 (24%), and EGFR (14%). Intratumoral CD8+ T-cell density was high in smokers (P = 0.02) and TP53-mutated tumors (P = 0.02) and low in BRAF-mutated tumors (P = 0.005). Intratumoral mDC density was high with low pathological tumor stage (P = 0.01) and low with STK11 mutation (P = 0.004). Intratumoral neutrophil density was high and low with BRAF mutation (P = 0.04) and EGFR mutation (P = 0.02), respectively. Intratumoral macrophage density was low with EGFR mutation (P = 0.01). Intratumoral CD8+ T-cell and mDC densities remained strong independent markers of overall survival (P = 0.001 and P = 0.02, respectively). CONCLUSIONS: Intratumoral immune cell densities (mDCs, CD8+ T cells, neutrophils, macrophages) were significantly associated with molecular alterations in adenocarcinoma underlying the interactions between cancer cells and their microenvironment.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Estudios de Cohortes , Femenino , Humanos , Pulmón/inmunología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
RATIONALE: It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. OBJECTIVES: To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC. METHODS: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA. MEASUREMENTS AND MAIN RESULTS: Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. CONCLUSIONS: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.
Asunto(s)
Subgrupos de Linfocitos B/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inmunidad Humoral , Neoplasias Pulmonares/inmunología , Biomarcadores/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Cohortes , Células Dendríticas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/mortalidad , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the anti-tumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship.
Asunto(s)
Autoinmunidad , Neoplasias , Humanos , Autoanticuerpos , Neoplasias/tratamiento farmacológico , Autoantígenos , Anticuerpos Monoclonales/uso terapéutico , Microambiente TumoralRESUMEN
One billion people worldwide get flu every year, including patients with non-small cell lung cancer (NSCLC). However, the impact of acute influenza A virus (IAV) infection on the composition of the tumor microenvironment (TME) and the clinical outcome of patients with NSCLC is largely unknown. We set out to understand how IAV load impacts cancer growth and modifies cellular and molecular players in the TME. Herein, we report that IAV can infect both tumor and immune cells, resulting in a long-term protumoral effect in tumor-bearing mice. Mechanistically, IAV impaired tumor-specific T-cell responses, led to the exhaustion of memory CD8+ T cells and induced PD-L1 expression on tumor cells. IAV infection modulated the transcriptomic profile of the TME, fine-tuning it toward immunosuppression, carcinogenesis, and lipid and drug metabolism. Consistent with these data, the transcriptional module induced by IAV infection in tumor cells in tumor-bearing mice was also found in human patients with lung adenocarcinoma and correlated with poor overall survival. In conclusion, we found that IAV infection worsened lung tumor progression by reprogramming the TME toward a more aggressive state.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Virus de la Influenza A , Gripe Humana , Neoplasias Pulmonares , Infecciones por Orthomyxoviridae , Humanos , Animales , Ratones , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Microambiente Tumoral , Linfocitos T CD8-positivos , Pulmón , Infecciones por Orthomyxoviridae/patologíaRESUMEN
Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumors arising in mucosal tissues may progress in an inflammatory context linked to local viral and/or bacterial infections. At the opposite, tumors developing in immunoprivileged sites are protected from microorganisms and grow in an immunosuppressive environment. In the present review, we summarize and present our recent data on the influence of infectious context and immune cell infiltration organization in human Non-Small Cell Lung Cancers (NSCLC) progression. We show that stimulation of tumor cells by TLR for viral ssRNA, such as TLR7/8, or bacteria, such as TLR4, promotes cell survival and induces chemoresistance. On the opposite, stimulation by TLR3, receptor for double-stranded viral RNA, decreases tumor cell viability and induces chemosensitivity in some lung tumor cell lines. Since fresh lung tumor cells exhibit a gene expression profile characteristic of TLR-stimulated lung tumor cell lines, we suspect that viral and bacterial influence may not only act on the host immune system but also directly on tumor growth and sensitivity to chemotherapy. The stroma of NSCLC contains tertiary lymphoid structures (or Tumor-induced Bronchus-Associated Lymphoid Tissues (Ti-BALT)) with mature DC, follicular DC, and T and B cells. Two subsets of immature DC, Langerhans cells (LC) and interstitial DC (intDC), were detected in the tumor nests and the stroma, respectively. Here, we show that the densities of the three DC subsets, mature DC, LC, and intDC, are highly predictive of disease-specific survival in a series of 74 early-stage NSCLC patients. We hypothesize that the mature DC may derive from local activation and migration of the immature DC--and especially LC which contact the tumor cells--to the tertiary lymphoid structures, after sampling and processing of the tumor antigens. In view of the prominent role of DC in the immune response, we suggest that the microenvironment of early-stage NSCLC may allow the in situ activation of the adaptive response. Finally, we find that the eyes or brain of mice with growing B cell lymphoma are infiltrated with T cells and that the cytokines produced ex vivo by the tumoral tissues have an impaired Th1 cytokine profile. Our work illustrates that the host and external tumor microenvironments are multifaceted and strongly influence tumor progression and anti-tumor immune responses.
Asunto(s)
Microambiente Tumoral , Animales , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Células Dendríticas/inmunología , Humanos , Linfoma/inmunología , Linfoma/patología , Receptores Toll-Like/metabolismoRESUMEN
The interplay between tumors and their immunologic microenvironment is complex and difficult to decipher, but its understanding is of seminal importance for the development of novel prognostic markers and therapeutic strategies. This chapter discusses tumor-immune interactions in several human cancers that illustrate various aspects of this complexity and proposes an integrated scheme of the impact of local immune reactions on clinical outcome. Thus, the fact that a strong infiltration of memory T cells with a Th1 and cytotoxic pattern is the strongest predictor for recurrence and metastasis is exemplified in colorectal cancer in which intratumoral chemokines shape an efficient immune reaction. Based on these data, we propose an immune score that predicts recurrence in early stage (UICC-TNM stage I-II) cancers. Studies on non-small lung cancers have confirmed findings of colorectal cancers and have addressed the question of the sites where antitumor immune reactions may take place. Tertiary lymphoid structures (TLS) adjacent to the tumor nest are sites of intense activity with mature dendritic cells in contact with T cells and germinal-like centers with proliferating B cells. The large number of these TLS being correlated with disease specific and overall survival tempts to postulate that they are privileged sites to mount an efficient antitumor reaction. Inflammation is a major component of human tumors and chronic inflammation is generally of bad prognosis. Head and neck cancers are highly inflammatory and two ways to modulate inflammation in these diseases are presented here: soluble IL-15 receptor α (IL-15 Rα) increases the pro-inflammatory effect of IL-15 and aggravates inflammation resulting in poor prognosis when found at high levels in the plasma of patients. By contrast, infiltration of regulatory T cells is paradoxically beneficial for local control of head and neck tumors, probably by "cooling down" the inflammatory process. The modulation of other aspects of innate immunity may also result in paradoxical effects such as the signaling through Toll like receptors 7 and 8 expressed on lung tumor cells which induce an aggressive tumoral phenotype. Finally, the analysis of primary intraocular lymphoma, which develops in the eye, exemplifies the induction of an antitumor immune reaction in an "immune sanctuary," presenting all the complexities of the tumor-immune interplay in "open" tissues such as the colon or the lung.
Asunto(s)
Neoplasias/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Neoplasias Pulmonares/inmunología , Linfocitos/inmunología , Linfoma/inmunología , Neoplasias/patología , Neoplasias/terapia , Pronóstico , Receptores Toll-Like/fisiologíaRESUMEN
OBJECTIVE: Studies suggest the implication of CD16(+) subpopulations (CD14(+)CD16(+), CD14(dim)CD16(+)) in inflammatory diseases. We aimed to determine the frequency of these subpopulations during weight loss in obesity and diabetes, conditions associated with changes in systemic inflammation, and we tested the link with subclinical atherosclerosis. METHODS AND RESULTS: CD14(dim)CD16(+) and CD14(+)CD16(+) frequencies were measured by flow cytometry in lean subjects, obese subjects before and after a hypocaloric diet or gastric surgery, and obese diabetic subjects before and after gastric surgery. Both monocyte subsets were increased in obese subjects, with a significant enrichment of the CD14(dim)CD16(+) subpopulation in obese diabetic patients. Multivariate analysis demonstrated a link between the percentages of CD14(dim)CD16(+) monocytes and glycemia, independent of fat mass. Drastic weight loss led to a sharp decrease of this subset, the variations of which were strongly related to fat mass changes. A reduction of at least 5% of fat mass was sufficient to observe a significant decrease of CD14(dim)CD16(+) monocytes. A diminution of the CD14(+)CD16(+) subset was also observed during weight loss and was associated with a decrease in intima-media thickness. CONCLUSIONS: This work demonstrates a major impact of fat mass variations on CD14(dim)CD16(+) monocyte subsets and that the decrease in the CD14(+)CD16(+) subpopulation is linked to a reduction of subclinical atherosclerosis. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00476658.
Asunto(s)
Adiposidad , Aterosclerosis/inmunología , Restricción Calórica , Diabetes Mellitus Tipo 2/inmunología , Receptores de Lipopolisacáridos/sangre , Monocitos/inmunología , Obesidad/terapia , Receptores de IgG/sangre , Pérdida de Peso , Absorciometría de Fotón , Adulto , Análisis de Varianza , Enfermedades Asintomáticas , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Citometría de Flujo , Francia , Proteínas Ligadas a GPI/sangre , Derivación Gástrica , Humanos , Masculino , Persona de Mediana Edad , Obesidad/inmunología , Obesidad/fisiopatología , Estudios Prospectivos , Análisis de Regresión , Factores de Tiempo , Resultado del Tratamiento , UltrasonografíaRESUMEN
Autophagy is a self-degradative mechanism involved in many biological processes, including cell death, survival, proliferation or migration. In tumors, autophagy plays an important role in tumorigenesis as well as cancer progression and resistance to therapies. Usually, a high level of autophagy in malignant cells has been associated with tumor progression and poor prognostic for patients. However, the investigation of autophagy levels in patients remains difficult, especially because quantification of autophagy proteins is challenging in the tumor microenvironment. In this study, we analyzed the expression of autophagy genes in non-small cell lung (NSCLC) cancer patients using public datasets and revealed an autophagy gene signature for proliferative and immune-checkpoint-expressed malignant cells in lung adenocarcinoma (LUAD). Analysis of autophagy-related gene expression profiles in tumor and adjacent tissues revealed differential signatures, namely signature A (23 genes) and signature B (12 genes). Signature B correlated with a bad prognosis and poor overall and disease-specific survival. Univariate and multivariate analyses revealed that this signature was an independent factor for prognosis. Moreover, patients with high expression of signature B exhibited more genes related to proliferation and fewer genes related to immune cells or immune response. The analysis of datasets from sorted fresh tumor cells or single cells revealed that signature B is predominantly represented in malignant cells, with poor expression in pan-immune population or in fibroblast or endothelial cells. Interestingly, autophagy was increased in malignant cells exhibiting high levels of signature B, which correlated with an elevated expression of genes involved in cell proliferation and immune checkpoint signaling. Taken together, our analysis reveals a novel autophagy-based signature to define the metabolic and immunogenic status of malignant cells in LUAD.
RESUMEN
Autophagy is an important process for cellular homeostasis at critical steps of development or in response to environmental stress. In the context of cancers, autophagy has a significant impact on tumor occurrence and tumor cell growth. On the one hand, autophagy limits the transformation of precancerous cells into cancer cells at an early stage. However, on the other hand, it promotes cell survival, cell proliferation, metastasis and resistance to anti-tumor therapies in more advanced tumors. Autophagy can be induced by a variety of extracellular and intracellular stimulus. Viral infections have often been associated with a modulation of autophagy, with variable impacts on viral replication and on the survival of infected cells depending on the model studied. In a tumor context, the modulation of autophagy induced by the viral infection of tumor cells seems to have a significant impact on tumor progression. The aim of this review article is to present recent findings regarding the consequences of autophagy disturbance by viral infections on tumor behavior.
TITLE: L'autophagie modulée par les virus - Un rôle dans la progression tumorale. ABSTRACT: L'autophagie est un processus métabolique important pour maintenir l'homéostasie cellulaire à des moments critiques du développement et/ou en réponse à un stress environnemental. Cela est particulièrement pertinent dans le cas des cancers, pour lesquels il a été montré que l'autophagie a un impact important sur leur survenue et sur la croissance tumorale. D'une part, elle limite la transformation cancéreuse des cellules précancéreuses à un stade précoce, mais, d'autre part, elle favorise la survie et la prolifération cellulaires, les métastases et la résistance aux thérapies anti-tumorales dans les tumeurs plus avancées. L'autophagie peut être induite par une grande variété de stimulus extracellulaires et intracellulaires. Les infections virales ont souvent été associées à une modulation de l'autophagie, dont l'impact sur la réplication virale ou la survie des cellules infectées diffère selon le modèle étudié. Dans un contexte tumoral, certains mécanismes moléculaires complexes par lesquels la modulation de l'autophagie par les virus peut influencer le développement des cellules précancéreuses ou cancéreuses ont été révélés. Cette revue présente les découvertes récentes concernant les répercussions d'une perturbation de l'autophagie par l'infection virale sur la survenue et la progression des tumeurs cancéreuses.
Asunto(s)
Neoplasias , Virus , Autofagia , Humanos , Neoplasias/terapia , Procesos Neoplásicos , Replicación ViralRESUMEN
INTRODUCTION: SMARCA4/BRG1 loss of expression occurs in 5-10% of non-small cell lung carcinomas (NSCLC). We investigated the pathological, molecular and immune environment characteristics of this deficiency among NSCLC, its impact on overall survival (OS) of resected patients and the sensitivity to anti-PD1 inhibitors in metastatic patients. MATERIALS AND METHODS: BRG1 expression was assessed by immunohistochemistry to identify SMARCA4-deficient NSCLC (SD-NSCLC) from the cancer tissue collection of Cochin Hospital (Paris, France). Molecular profiles were analyzed by targeted NGS covering 28 genes in 63 resected SD-NSCLC. The balance of immune cells between CD8+, FOXP3+ cells and neutrophils (CD66b+) was characterized by multiplex immunohistochemistry and compared to non-SD NSCLC. Clinical outcome after anti-PD-1 therapy was evaluated in 7 SD-NSCLC out of 77 NSCLC patients. RESULTS: SD-NSCLCs were more commonly found in TTF1-negative high-grade adenocarcinomas and pleomorphic carcinomas. They were associated with few targetable alterations (KRAS G12C and MET amplification). Their immune environment was characterized by an increased of FOXP3+ cell and neutrophil densities, but not of CD8+ T cells, compared to non-SD NSCLC. SD-NSCLC patients had a significantly shorter OS in early stages of resected patients and in metastatic patients treated by anti-PD1 treatment. CONCLUSION: BRG1-loss in NSCLC confers a poor prognosis and is associated with an immunosuppressive environment that could be responsible of limited efficacy to anti-PD1 inhibitors. The identification of SD-NSCLC by BRG1 immunohistochemistry is desirable for an optimal management of NSCLC patients.
Asunto(s)
Adenocarcinoma , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma/patología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , ADN Helicasas/genética , Factores de Transcripción Forkhead/genética , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Neutrófilos/patología , Proteínas Nucleares/genética , Factores de Transcripción/genéticaRESUMEN
Autophagy is a self-degradative process important for balancing cellular homeostasis at critical times in development and/or in response to nutrient stress. This is particularly relevant in tumor model in which autophagy has been demonstrated to have an important impact on tumor behavior. In one hand, autophagy limits tumor transformation of precancerous cells in early stage, and in the other hand, it favors the survival, proliferation, metastasis, and resistance to antitumor therapies in more advanced tumors. This catabolic machinery can be induced by an important variety of extra- and intracellular stimuli. For instance, viral infection has often been associated to autophagic modulation, and the role of autophagy in virus replication differs according to the virus studied. In the context of tumor development, virus-modulated autophagy can have an important impact on tumor cells' fate. Extensive analyses have shed light on the molecular and/or functional complex mechanisms by which virus-modulated autophagy influences precancerous or tumor cell development. This review includes an overview of discoveries describing the repercussions of an autophagy perturbation during viral infections on tumor behavior.