RESUMEN
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1ß (IL-1ß) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
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Proteínas Portadoras/inmunología , Diferenciación Celular/inmunología , Células Th2/inmunología , Transactivadores/inmunología , Animales , Asma/genética , Asma/inmunología , Asma/metabolismo , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Factores Reguladores del Interferón/metabolismo , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células 3T3 NIH , Proteína con Dominio Pirina 3 de la Familia NLR , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/inmunología , Unión Proteica/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/inmunología , Células Th2/metabolismo , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
The TH9 subset of helper T cells was initially shown to contribute to the induction of autoimmune and allergic diseases, but subsequent evidence has suggested that these cells also exert antitumor activities. However, the molecular events that account for their effector properties are elusive. Here we found that the transcription factor IRF1 enhanced the effector function of TH9 cells and dictated their anticancer properties. Under TH9-skewing conditions, interleukin 1ß (IL-1ß) induced phosphorylation of the transcription factor STAT1 and subsequent expression of IRF1, which bound to the promoters of Il9 and Il21 and enhanced secretion of the cytokines IL-9 and IL-21 from TH9 cells. Furthermore, IL-1ß-induced TH9 cells exerted potent anticancer functions in an IRF1- and IL-21-dependent manner. Our findings thus identify IRF1 as a target for controlling the function of TH9 cells.
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Factor 1 Regulador del Interferón/inmunología , Interleucinas/inmunología , Melanoma Experimental/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células 3T3 , Animales , Secuencia de Bases , Línea Celular , Femenino , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Factor 1 Regulador del Interferón/biosíntesis , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/antagonistas & inhibidores , Interleucina-10/inmunología , Interleucina-9/genética , Interleucina-9/inmunología , Interleucina-9/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/inmunología , Fosforilación/inmunología , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fyn/genética , Interferencia de ARN , ARN Interferente Pequeño , Factor de Transcripción STAT1/inmunología , Análisis de Secuencia de ARN , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Immune checkpoint inhibitors (ICIs) have improved the care of patients in multiple cancer types. However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deficiency are the only validated biomarkers of efficacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. Whole-exome sequencing was carried out on 154 metastatic or locally advanced cancers from different tumor types treated by immunotherapy. Clinical and genomic features were investigated using Cox regression models to explore their capacity to predict progression-free survival (PFS). The cohort was split into training and validation sets to assess validity of observations. Two predictive models were estimated using clinical and exome-derived variables, respectively. Stage at diagnosis, surgery before immunotherapy, number of lines before immunotherapy, pleuroperitoneal, bone or lung metastasis, and immune-related toxicity were selected to generate a clinical score. KRAS mutations, TMB, TCR clonality, and Shannon entropy were retained to generate an exome-derived score. The addition of the exome-derived score improved the prediction of prognosis compared with the clinical score alone. Exome-derived variables could be used to predict responses to ICI independently of tumor type and might be of value in improving patient selection for ICI therapy.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Exoma , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Pulmonares/genética , Mutación , Biomarcadores de Tumor/genética , Genómica , Inmunoterapia , Antígeno B7-H1/genéticaRESUMEN
PURPOSE: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes. PATIENTS AND METHODS: In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated. RESULTS: Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2- eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities. CONCLUSION: This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.
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Receptor ErbB-2 , Neoplasias de la Mama Triple Negativas , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudios Prospectivos , Genes BRCA2 , Genómica , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Carcinoma/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Femenino , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Mutación , Neoplasias Ováricas/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-ß expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-ß-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1ß, IL-6, and IL-23 but without TGF-ß did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-ß and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
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5'-Nucleotidasa/genética , Antígenos CD/genética , Apirasa/genética , Proteínas de Unión al ADN/inmunología , Factor de Transcripción STAT3/inmunología , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/inmunología , Animales , Sitios de Unión/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Interleucina-6/farmacología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th17/efectos de los fármacos , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.
Asunto(s)
Janus Quinasa 2/metabolismo , Donantes de Óxido Nítrico/farmacología , Nitroglicerina/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Invasividad Neoplásica/prevención & control , Donantes de Óxido Nítrico/uso terapéutico , Nitroglicerina/uso terapéutico , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
OBJECTIVE: Diagnostic tests, such as Immunoscore, predict prognosis in patients with colon cancer. However, additional prognostic markers could be detected on pathological slides using artificial intelligence tools. DESIGN: We have developed a software to detect colon tumour, healthy mucosa, stroma and immune cells on CD3 and CD8 stained slides. The lymphocyte density and surface area were quantified automatically in the tumour core (TC) and invasive margin (IM). Using a LASSO algorithm, DGMate (DiGital tuMor pArameTErs), we detected digital parameters within the tumour cells related to patient outcomes. RESULTS: Within the dataset of 1018 patients, we observed that a poorer relapse-free survival (RFS) was associated with high IM stromal area (HR 5.65; 95% CI 2.34 to 13.67; p<0.0001) and high DGMate (HR 2.72; 95% CI 1.92 to 3.85; p<0.001). Higher CD3+ TC, CD3+ IM and CD8+ TC densities were significantly associated with a longer RFS. Analysis of variance showed that CD3+ TC yielded a similar prognostic value to the classical CD3/CD8 Immunoscore (p=0.44). A combination of the IM stromal area, DGMate and CD3, designated 'DGMuneS', outperformed Immunoscore when used in estimating patients' prognosis (C-index=0.601 vs 0.578, p=0.04) and was independently associated with patient outcomes following Cox multivariate analysis. A predictive nomogram based on DGMuneS and clinical variables identified a group of patients with less than 10% relapse risk and another group with a 50% relapse risk. CONCLUSION: These findings suggest that artificial intelligence can potentially improve patient care by assisting pathologists in better defining stage III colon cancer patients' prognosis.
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Adenocarcinoma/patología , Inteligencia Artificial , Neoplasias del Colon/patología , Interpretación de Imagen Asistida por Computador , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Supervivencia sin Enfermedad , Humanos , Linfocitos Infiltrantes de Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , PronósticoRESUMEN
Colorectal cancer is a highly metastatic disease that could invade various distal organs and also the peritoneal cavity leading to peritoneal carcinomatosis. This is a terminal condition with poor prognosis and only palliative treatments such as cytoreductive surgery and intraperitoneal chemotherapy are proposed to some patients. However, clinicians use different parameters of treatments without any consensus. Here we decided to evaluate the effect of osmolarity in the efficacy of this procedure to kill colon cancer cells. We first show that a short exposure of platinum derivatives in hypotonic conditions is more efficient to decrease cell viability of human and murine colon cancer cells in vitro as compared to isotonic conditions. This is related to more important incorporation of platinum and the capacity of hypotonic stress to induce the copper transporter CTR1 oligomerization. Oxaliplatin in hypotonic conditions induces caspase-dependent cell death of colon cancer cells. Moreover, hypotonic conditions also modulate the capacity of oxaliplatin and cisplatin (but not carboplatin) to induce immunogenic cell death (ICD). In vivo, oxaliplatin in hypotonic conditions increases CD8+ T cell tumor infiltration and activation. Finally, in a murine peritoneal carcinomatosis model, oxaliplatin in hypotonic conditions is the only tested protocol which is able to slow down the appearance of tumor nodules and increase mice survival, while showing no effect in CD8+ T cells depleted mice or in immunodeficient mice. Altogether, our study provides new information both in vitro and in a preclinical model of peritoneal carcinomatosis, which highlights the importance of hypoosmolarity in intraperitoneal chemotherapy.
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Linfocitos T CD8-positivos/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Presión Osmótica , Oxaliplatino/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/inmunología , Femenino , Células HCT116 , Células HT29 , Humanos , Inyecciones Intraperitoneales , Activación de Linfocitos/efectos de los fármacos , Ratones , Oxaliplatino/farmacología , Neoplasias Peritoneales/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Since the publication of this paper, the authors noticed that Corentin Richard was not credited as contributing equally to the paper. He should be considered as a joint first author with Jean-David Fumet.
RESUMEN
BACKGROUND: No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC). METHODS: We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types. RESULTS: In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures. CONCLUSION: CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.
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Antígeno B7-H1/análisis , Antígenos CD8/análisis , Linfocitos T CD8-positivos/citología , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Supervivencia sin Progresión , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Antígenos CD8/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , ARN Mensajero/genética , Estudios RetrospectivosRESUMEN
The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer.
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Neoplasias de la Mama/inmunología , Inmunoterapia/métodos , Antígenos de Neoplasias/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Células Dendríticas/fisiología , Femenino , Humanos , Inflamación , Modelos Inmunológicos , Terapia Molecular Dirigida , Monitorización Inmunológica , Mucina-1/inmunología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/inmunología , Fagocitosis , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor ErbB-2/inmunología , Escape del Tumor/inmunología , Microambiente TumoralRESUMEN
BACKGROUND: T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables. METHODS: We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression. FINDINGS: CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS. INTERPRETATION: In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination. FUNDING: This research received no external funding.
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Neoplasias del Colon , Linfocitos Infiltrantes de Tumor , Aprendizaje Automático , Estadificación de Neoplasias , Humanos , Neoplasias del Colon/mortalidad , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Pronóstico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Stratification of the prognosis of pancreatic cancer (PDAC) patients treated by surgery is based solely on clinical variables, such as tumor stage and node status. The development of biomarkers of relapse is needed, especially to drive administration of adjuvant therapy in this at-risk population. Our study evaluates the prognostic performance of a CD3- and CD8-based immune score. CD3, CD8 and Foxp3 expression were evaluated on whole slides in two retrospective PDAC cohorts totaling 334 patients. For this study, we developed an immune score to estimate CD3 and CD8 infiltration in both tumor core and invasive margin using computer-guided analysis with QuPath software. Variables were combined in a dichotomous immune score. The association between immune and clinical scores, and both PFS and OS was investigated. We observed that a dichotomous immune score predicts both PFS and OS of localized PDAC. By univariate and multivariate analysis, immune score, tumor grade, adjuvant therapy, lymph node status, and adjuvant chemotherapy administration were associated with PFS and OS. We subsequently associated the PDAC immune score and clinical variables in a combined score. This combined score predicted patient outcomes independently of adjuvant or neoadjuvant treatment, and improved patient prognostic prediction compared to clinical variables or immune score alone.
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Terapia Neoadyuvante , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Pronóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Adyuvantes Inmunológicos , Linfocitos T CD8-positivos/patologíaRESUMEN
A patient with a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated metastatic non-small cell lung cancer (NSCLC) experienced a multisite radiological progression at 3 months after initiation of chemoimmunotherapy as first-line treatment for metastatic disease. After the radiological progression, while she was not undergoing treatment, the patient had spontaneous lesions shrinkage and further achieved a prolonged complete response. Genomic and transcriptomic data collected at baseline and at the time of pseudoprogression allowed us to biologically characterize this rare response pattern. We observed the presence of a tumor-specific T-cell response against tumor-specific neoantigens (TNAs). Endogenous retroviruses (ERVs) expression following chemoimmunotherapy was also observed, concurrent with biological features of an anti-viral-like innate immune response with type I IFN signaling and production of CXCR3-associated chemokines. This is the first biological characterization of a NSCLC pseudoprogression under chemoimmunotherapy followed by a prolonged complete response in a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated NSCLC. These clinical and biological data underline that even patients with multiple factors of resistance to immune checkpoint inhibitors could trigger a tumor-specific immune response to tumor neoantigen, leading to complete eradication of the tumor and probably a vaccinal immune response.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Progresión de la Enfermedad , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Antígeno B7-H1/genética , Femenino , Persona de Mediana Edad , Biomarcadores de TumorRESUMEN
The detection of tumour gene mutations by DNA or RNA sequencing is crucial for the prescription of effective targeted therapies. Recent developments showed promising results for tumoral mutational status prediction using new deep learning based methods on histopathological images. However, it is still unknown whether these methods can be useful aside from sequencing methods for efficient population diagnosis. In this retrospective study, we use a standard prediction pipeline based on a convolutional neural network for the detection of cancer driver genomic alterations in The Cancer Genome Atlas (TCGA) breast (BRCA, n = 719), lung (LUAD, n = 541) and colon (COAD, n = 459) cancer datasets. We propose 3 diagnostic strategies using deep learning methods as first-line diagnostic tools. Focusing on cancer driver genes such as KRAS, EGFR or TP53, we show that these methods help reduce DNA sequencing by up to 49.9% with a high sensitivity (95%). In a context of limited resources, these methods increase sensitivity up to 69.8% at a 30% capacity of DNA sequencing tests, up to 85.1% at a 50% capacity, and up to 91.8% at a 70% capacity. These methods can also be used to prioritize patients with a positive predictive value up to 90.6% in the 10% patient most at risk of being mutated. Limitations of this study include the lack of external validation on non-TCGA data, dependence on prevalence of mutations in datasets, and use of a standard DL method on a limited dataset. Future studies using state-of-the-art methods and larger datasets are needed for better evaluation and clinical implementation.
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Aprendizaje Profundo , Humanos , Estudios Retrospectivos , Redes Neurales de la Computación , Mutación , OncogenesRESUMEN
There is little data concerning the implications of PIK3CA mutations outside of the known hotspots described in ER+/HER2- metastatic breast cancer (mBC). Similarly, PIK3R1 mutations could also lead to activation of PI3K pathway, but are poorly described. We determined the incidence and type of all somatic PIK3CA and PIK3R1 mutations by whole exome sequencing (WES) in a pan-cancer cohort of 1200 patients. Activation of the PI3K pathway was studied using phospho-AKT immunohistochemistry. Associations between PIK3CA/PIK3R1 mutations and response to chemotherapy were studied in mBC cases. We found 141 patients (11.8%) with a PIK3CA and/or PIK3R1 mutation across 20 different cancer types. The main cancer subtype was mBC (45.4%). Eighty-four mutations (62.2%) occurred in the three described hotspots; 51 mutations occurred outside of these hotspots. In total, 78.4% were considered activating or probably activating. Among PIK3R1 mutations, 20% were loss of function mutations, leading to a constitutional activation of the pathway. Phospho-AKT quantification in tumor samples was in favor of activation of the PI3K pathway in the majority of mutated tumors, regardless of mutation type. In ER+/HER2- mBC, first line chemotherapy efficacy was similar for PIK3CA-mutated and PIK3CA-WT tumors, whereas in triple negative mBC, chemotherapy appeared to be more effective in PIK3CA-WT tumors. In this large, real-life pan-cancer patient cohort, our results indicate that PIK3CA/PIK3R1 mutations are widely spread, and plead in favour of evaluating the efficacy of PI3K inhibitors outside of ER+/HER2- mBC and outside of hotspot mutations.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Resultado del Tratamiento , Factores de Transcripción/genética , Mutación , Fosfatidilinositol 3-Quinasa Clase Ia/genéticaRESUMEN
(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8+ lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1low. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.
RESUMEN
BACKGROUND AND AIMS: In colorectal cancer (CRC), HER2 targeting is a promising treatment and immune infiltrate is an important area of research and strategy. Data regarding HER2 status and immune infiltrate are lacking. The aim of this study was to compare the immune infiltrate between HER2 amplified and non-amplified categories in proficient MisMatchRepair (pMMR)/microsatellite stable (MSS) CRC. METHODS: HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization were performed in a retrospective series of 654 CRC. Lymphocyte infiltrate was analysed by anti-CD3, CD8 and CD4 IHC and evaluated digitally using QuPath software. RESULTS: Among the 654 CRC, we first observed a decreased CD3+ and CD8+ infiltrate between HER2 amplified (all IHC 3+ except one 2+) and non-amplified HER2 2+ IHC CRC (p = 0.059 and 0.072 respectively). A supplementary analysis of 258 pMMR/MSS CRC from the previous cohort, displaying all the IHC scores (0, 1+, 2+, 3+), showed a lower CD3+ infiltrate between HER2 amplified versus HER2 0 (p = 0.002), 1+ (p = 0.088) and non-amplified 2+ (p = 0.081) IHC cases. CONCLUSIONS: Our original findings suggest that in pMMR/MSS CRC, the immune infiltrate is reduced in HER2 amplified versus other HER2 categories. These data might be useful for future strategies combining anti-HER2 treatments and immune checkpoint inhibitors and need to be confirmed in larger CRC cohorts.