RESUMEN
Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.
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Carcinoma Ductal Pancreático , Monocitos , Neoplasias Pancreáticas , Macrófagos Asociados a Tumores , Animales , Monocitos/inmunología , Humanos , Ratones , Macrófagos Asociados a Tumores/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
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.
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Autoinmunidad , Neoplasias , Humanos , Autoanticuerpos , Neoplasias/tratamiento farmacológico , Autoantígenos , Anticuerpos Monoclonales/uso terapéutico , Microambiente TumoralRESUMEN
PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. EXPERIMENTAL DESIGN: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. RESULTS: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial-mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. CONCLUSIONS: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients' treatments. See related commentary by Zhou and Kim, p. 1170.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nivolumab/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Ipilimumab/administración & dosificación , Metilación de ADN , Fenotipo , Microambiente Tumoral/genética , Oxigenasas de Función Mixta , Proteínas Proto-Oncogénicas/genéticaAsunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Humanos , Ipilimumab/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Nivolumab/uso terapéutico , Sunitinib/uso terapéuticoRESUMEN
BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.
Asunto(s)
Carcinoma de Células Renales , Nivolumab , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Ipilimumab , Lipasa , Masculino , Estadificación de Neoplasias , Nivolumab/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Sunitinib , Microambiente TumoralRESUMEN
The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
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Carcinoma de Células Renales , Neoplasias Renales , Estructuras Linfoides Terciarias , Carcinoma de Células Renales/terapia , Femenino , Humanos , Inmunoglobulina G , Neoplasias Renales/terapia , Masculino , Células Plasmáticas , Estructuras Linfoides Terciarias/patología , Microambiente TumoralRESUMEN
The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population. TAM expressing C1q correlate with T cell exhaustion and poor prognosis in numerous cancers. Herein, we discuss the plural roles of C1q in these macrophages and how it could drive cancer progression.
Asunto(s)
Complemento C1q , Neoplasias , Humanos , MacrófagosRESUMEN
Whereas T cells have been considered the major immune cells of the tumor microenvironment able to induce tumor regression and control cancer clinical outcome, a burst of recent publications pointed to the fact that B cells may also play a prominent role. Activated in germinal centers of tertiary lymphoid structures, B cells can directly present tumor-associated antigens to T cells or produce antibodies that increase antigen presentation to T cells or kill tumor cells, resulting in a beneficial clinical impact. Immune complexes can also increase inflammation, angiogenesis, and immunosuppression via macrophage and complement activation, resulting in deleterious impact.
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Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Neoplasias/inmunología , Neovascularización Patológica/inmunología , Microambiente Tumoral/inmunología , Animales , Linfocitos B/patología , Activación de Complemento , Humanos , Inflamación/inmunología , Inflamación/patología , Macrófagos/patología , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica/patología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells. Furthermore, recent studies demonstrated that the presence in tumors of B cells and TLS are associated with favorable outcome in patients treated by immunotherapy, unraveling TLS as a new predictive marker of anti-tumor response human cancers. This review encompasses the characteristics and functions of TLS and of B cells in human tumors, their prognostic and theranostic impact and summarizes the mouse models used to induce TLS neogenesis in tumors.
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Linfocitos B/inmunología , Biomarcadores de Tumor/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Linfocitos T/inmunología , Estructuras Linfoides Terciarias/inmunología , Animales , Biomarcadores Farmacológicos , Humanos , Inmunomodulación , Neoplasias/inmunología , Microambiente TumoralRESUMEN
Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor ß superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.
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Factor 15 de Diferenciación de Crecimiento/inmunología , Inmunomodulación , Animales , Enfermedades Autoinmunes/inmunología , Biomarcadores/análisis , Femenino , Homeostasis , Humanos , Inhibidores de Puntos de Control Inmunológico , Ratones , Infarto del Miocardio/inmunología , Neoplasias/inmunología , Placenta/inmunología , EmbarazoAsunto(s)
Linfocitos B/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Estructuras Linfoides Terciarias/inmunología , Microambiente Tumoral/inmunología , Linfocitos B/patología , Biomarcadores , Humanos , Neoplasias/mortalidad , Neoplasias/patología , Neoplasias/terapia , Sarcoma/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Estructuras Linfoides Terciarias/patología , Resultado del TratamientoRESUMEN
The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient's clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling.
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Activación de Complemento , Proteínas del Sistema Complemento/inmunología , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Animales , Vacunas contra el Cáncer , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Genoma Humano , Humanos , Ratones , Pronóstico , Linfocitos T/inmunología , TranscriptomaRESUMEN
Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.
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Neoplasias/inmunología , Neoplasias/terapia , Estructuras Linfoides Terciarias/patología , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inmunoterapia , Inflamación/inmunología , Inflamación/patología , Neoplasias/patología , Pronóstico , Estructuras Linfoides Terciarias/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
In colorectal cancer (CRC), T-cell checkpoint blockade is only effective in patients diagnosed with mismatch repair-deficient (MMR-d) cancers. However, defects in Human Leukocyte Antigen (HLA) class I expression were reported to occur in most MMR-d CRCs, which would preclude antigen presentation in these tumours, considered essential for the clinical activity of this immunotherapeutic modality. We revisited this paradox by characterising HLA class I expression in two independent cohorts of CRC. We determined that loss of HLA class I expression occurred in the majority (73-78%) of MMR-d cases. This phenotype was rare in CRC liver metastases, irrespective of MMR status, whereas weak, inducible expression of HLA class I molecules was frequent in liver lesions. We propose that HLA class I is an important determinant of metastatic homing in CRCs. This observation is paramount to understand CRC carcinogenesis and for the application of immunotherapies in the metastatic setting.
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Neoplasias Colorrectales/terapia , Genes MHC Clase I/genética , Inmunoterapia , Linfocitos T/inmunología , Presentación de Antígeno/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Carcinogénesis/genética , Carcinogénesis/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Genes cdc/efectos de los fármacos , Genes cdc/inmunología , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/inmunologíaRESUMEN
Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8+ or CD20+ cells are associated with clinical progression. Patients with at least 1% PD-L1+ tumor cells had shorter metastasis-free survival than those with PD-L1- tumors (p=0.008, log-rank test). Univariate Cox regression showed that patients with PD-L1+ tumors had almost four times the risk of experiencing distant metastases than those with PD-L1- tumors (hazard ratio 3.90). In addition, we found that PD-L1 expression was significantly associated with CD8+ T-cell density, but not with CD20+ B-cell density. While these results need to be confirmed in larger studies, they show that PD-L1 and CD8 may be used as biomarkers for node-positive patients at high risk of progression. The study also provides a rationale for selecting patients with node-positive PCa who might benefit the most from adjuvant immunotherapies. PATIENT SUMMARY: None of the available biomarkers can identify node-positive prostate cancer that will recur after surgery. We found that expression of PD-L1 by tumor cells and a high density of CD8+ T cells in tumor are associated with a higher risk of clinical progression in men with node-positive prostate cancer.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/metabolismo , Neoplasias de la Próstata/patología , Adyuvantes Inmunológicos/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Recurrencia Local de Neoplasia/epidemiología , Prostatectomía , Neoplasias de la Próstata/secundario , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver. METHODS: We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort). RESULTS: TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2â¯years after surgery, hazard ratio 0.46, pâ¯=â¯0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, pâ¯=â¯0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed. CONCLUSIONS: We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity. LAY SUMMARY: Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/patología , Estructuras Linfoides Terciarias/patología , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Estudios Retrospectivos , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/metabolismo , Factores de TiempoRESUMEN
The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
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Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunología , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/patología , Proliferación Celular/genética , Células Endoteliales/inmunología , Células Endoteliales/patología , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias/patología , Linfocitos T Citotóxicos/patologíaRESUMEN
A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.
Asunto(s)
Carcinoma/inmunología , Carcinoma/patología , Células Dendríticas/inmunología , Células Dendríticas/patología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Carcinoma/mortalidad , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patologíaRESUMEN
Fc-receptors for immunoglobulin G (FcγRs) mediate a variety of effector and regulatory mechanisms in the immune system. N-glycosylation of FcγRs critically affects their functions which is well exemplified by antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis mediated by homologous FcγRIIIa and FcγRIIIb, respectively. Although several reports describe N-glycosylation profiles of recombinant FcγRIII glycoproteins, much remains unknown regarding their native glycoforms. Here we performed site-specific N-glycosylation profiling of a soluble form of FcγRIIIb purified from human serum based on mass spectrometric analysis. Our data indicate a distinct and common tendency of the glycoforms exhibited at each N-glycosylation site between the native and the previously reported recombinant FcγRIII glycoproteins. Among the six N-glycosylation sites of serum soluble FcγRIIIb, Asn45 was shown to be exclusively occupied by high-mannose-type oligosaccharides, whereas the remaining sites were solely modified by the complex-type oligosaccharides with sialic acid and fucose residues. The results of our endogenous FcγRIII glycoform analyses are important for the optimization of therapeutic antibody efficacy.