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Non-muscle-invasive bladder cancer (NMIBC) presents management challenges due to its high recurrence rate and a complex tumor microenvironment (TME). This study investigated the effects of OncoTherad® (MRB-CFI1) nanoimmunotherapy on the TME of BCG-unresponsive NMIBC, focusing on alterations in monoamine oxidases (MAO-A and MAO-B) and immune markers: CD163, FOXP3, CD8, and CX3CR1. A comparative analysis of immunoreactivities was made before and after OncoTherad® treatment and an immune score (IS) was established to evaluate the correlation between immunological changes and clinical outcomes. Forty bladder biopsies of twenty patients were divided into 2 groups (n = 20/group): 1 (pre-treatment biopsies); and 2 (post-treatment biopsies). Our results showed stable MAO-A levels but a significant (p < 0.05) decrease in MAO-B immunoreactivity after treatment, suggesting OncoTherad®'s efficacy in targeting the tumor-promoting and immunosuppressive functions of MAO-B. Significant (p < 0.05) reductions in CD163 and FOXP3 immunoreactivities were seen in post-treatment biopsies, indicating a decreased presence of M2 macrophages and Tregs. Corroborating with these results, we observed reductions in tumor histological grading, focality and size, factors that collectively enhanced recurrence-free survival (RFS) and pathological complete response (PCR). Moreover, elevated IFN-γ immunoreactivities in treated biopsies correlated with increased counts of CD8+ T cells and higher CX3CR1 expression, underscoring OncoTherad®'s enhancement of cytotoxic T cell functionality and overall antitumor immunity. The IS revealed improvements in immune responses post-treatment, with higher scores associated with better RFS and PCR outcomes. These findings validate OncoTherad®'s capability to modify the bladder cancer microenvironment favorably, promoting effective immune surveillance and response.
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Inmunoterapia , Linfocitos Infiltrantes de Tumor , Monoaminooxidasa , Microambiente Tumoral , Macrófagos Asociados a Tumores , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Masculino , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Anciano , Inmunoterapia/métodos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/efectos de los fármacos , Monoaminooxidasa/metabolismo , Anciano de 80 o más Años , Neoplasias Vesicales sin Invasión MuscularRESUMEN
Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.
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5'-Nucleotidasa , Neoplasias de la Próstata , Transducción de Señal , Humanos , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/inmunología , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/inmunología , Microambiente Tumoral/inmunología , Adenosina/metabolismo , Inmunoterapia/métodos , Terapia Molecular DirigidaRESUMEN
BACKGROUND: To comprehensively analyze the clinical significance of Immune Checkpoint-Related Genes (ICRGs) in Pancreatic Adenocarcinoma (PAAD). METHOD: PAAD tissues and normal pancreatic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and 283 ICRGs were integrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome datasets. Unsupervised clustering was used to obtain potential ICRGs-based PAAD subtypes. Wilcoxon test was performed to screen Differentially Expressed ICRGs (DEICRGs), while cox regression analyses were utilized to identify prognosis-related ICRGs and clinicopathological factors, and construct the corresponding models. The Tumor Immune Microenvironment (TIME) was evaluated. Moreover, the authors performed enrichment analysis, Gene Set Enrichment Analysis (GSEA), and transcription factor regulatory networks to realize underlying mechanisms. RESULTS: Three ICRGs-based PAAD subtypes were identified, and they were associated with three ESTIMATE scores, a Tumor Microenvironment (TMB) score, 14 therapeutic immune checkpoints, and infiltration levels of seven immune cells. On top of that, the authors constructed two signatures based on DEICRGs to predict the Overall Survival (OS) (Area Under the ROC Curve [AUC: 0.741â¼0.778]) and Progression-Free Survival (PFS) (AUC: 0.746â¼0.831) of patients. Two nomograms were established by combining clinical variables and signatures. In addition, the authors found higher infiltration of naïve B cells and CD8+ T-cells in low-risk PAAD patients, and higher infiltration of suppressive immune cells and cancer-related signaling pathways in high-risk PAAD patients. CONCLUSION: The present study suggested that ICRGs were associated with TIME formation and prognosis of PAAD patients, which may serve as novel clinical biomarkers and therapeutic targets.
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Adenocarcinoma , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de Punto de Control Inmunitario/genética , AncianoRESUMEN
PURPOSE: To assess the association between tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) samples and disease recurrence. METHODS: This retrospective cohort study included women aged 18 years and older who underwent treatment between January 2007 and December 2020. Male patients, individuals diagnosed with invasive or microinvasive disease based on anatomopathological examination of surgical specimens, and those with a personal history of any other cancers were excluded. Additionally, the presence of "touching TILs" (lymphocytes in direct contact with tumor cells) and periductal desmoplasia were evaluated as complementary methods to represent the immunological microenvironment. The primary outcome was relapse-free survival based on TIL quantification adjusted for potential confounders. Pathologists assessed TILs in the sample with the highest tumor representation and quantified them as a percentage. Survival was evaluated using KaplanâMeier curves, log-rank tests, and Cox regression models. RESULTS: A total of 191 patients met the eligibility criteria. The mean follow-up duration was 77.2 months, with a recurrence rate of 9.2%. Patients with TILs ≥ 17% had a greater risk of recurrence (HR 2.97, 95% CI 1.17-7.51; p = 0.02). Additionally, focal necrosis (HR 6.4, 95% CI 1.39-34.71; p = 0.018) or comedonecrosis (HR 4.53, 95% CI 1.34-15.28; p = 0.015) were associated with increased recurrence risk. According to the multivariate model, comedonecrosis and TILs ≥ 17% were significantly associated with recurrence (p = 0.034 and p = 0.035, respectively). Regarding the evaluations of "touching TILs" and periductal desmoplasia, no statistical significance was found when assessing their association with disease recurrence. CONCLUSION: In our cohort, a high percentage of TILs (≥ 17%) and the presence of comedonecrosis were independently associated with DCIS recurrence.
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Biomarcadores de Tumor , Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Linfocitos Infiltrantes de Tumor , Recurrencia Local de Neoplasia , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Estudios Retrospectivos , Pronóstico , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/mortalidad , Recurrencia Local de Neoplasia/patología , Anciano , Adulto , Masculino , Microambiente Tumoral/inmunologíaRESUMEN
Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment responses due to their remarkable plasticity and tumorigenic behaviors. Here, we integrate single-cell RNA-sequencing data from different cancer types, identifying 29 MDC subpopulations within the tumor microenvironment. Our analysis reveals abnormally expanded MDC subpopulations across various tumors and distinguishes cell states that have often been grouped together, such as TREM2+ and FOLR2+ subpopulations. Using deconvolution approaches, we identify five subpopulations as independent prognostic markers, including states co-expressing TREM2 and PD-1, and FOLR2 and PDL-2. Additionally, TREM2 alone does not reliably predict cancer prognosis, as other TREM2+ macrophages show varied associations with prognosis depending on local cues. Validation in independent cohorts confirms that FOLR2-expressing macrophages correlate with poor clinical outcomes in ovarian and triple-negative breast cancers. This comprehensive MDC atlas offers valuable insights and a foundation for futher analyses, advancing strategies for treating solid cancers.
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Glicoproteínas de Membrana , Células Mieloides , Neoplasias , Receptores Inmunológicos , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Análisis de la Célula Individual/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Células Mieloides/metabolismo , Células Mieloides/patología , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Pronóstico , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Femenino , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genéticaRESUMEN
INTRODUCTION: Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics. METHODS: Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma. RESULTS: CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated. CONCLUSIONS: PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.
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Adenocarcinoma , Antígeno B7-H1 , Antígenos HLA-G , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Antígeno B7-H1/metabolismo , Antígenos HLA-G/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Pronóstico , Linfocitos T CD8-positivos/inmunología , Adulto , Linfocitos T Reguladores/inmunología , Anciano de 80 o más Años , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patologíaRESUMEN
Colorectal cancer (CRC) is a major cause of cancer-related deaths globally. While treatment advancements have improved survival rates, primarily through targeted therapies based on KRAS, NRAS, and BRAF mutations, personalized treatment strategies for CRC remain limited. Immunotherapy, mainly immune checkpoint blockade, has shown efficacy in various cancers but is effective in only a small subset of patients with CRC with deficient mismatch repair (dMMR) proteins or high microsatellite instability (MSI). Recent research has challenged the notion that CRC is immunologically inert, revealing subsets with high immunogenicity and diverse lymphocytic infiltration. Identifying precise biomarkers beyond dMMR and MSI is crucial to expanding immunotherapy benefits. Hence, exploration has extended to various biomarker sources, such as the tumor microenvironment, genomic markers, and gut microbiota. Recent studies have introduced a novel classification system, consensus molecular subtypes, that aids in identifying patients with CRC with an immunogenic profile. These findings underscore the necessity of moving beyond single biomarkers and toward a comprehensive understanding of the immunological landscape in CRC, facilitating the development of more effective, personalized therapies.
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Neoplasias Colorrectales , Inmunoterapia , Humanos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/genética , Inmunoterapia/métodos , Biomarcadores de Tumor/genética , Microambiente Tumoral/inmunología , Inestabilidad de MicrosatélitesRESUMEN
The tumor microenvironment (TME) harbors several cell types, such as tumor cells, immune cells, and non-immune cells. These cells communicate through several mechanisms, such as cell-cell contact, cytokines, chemokines, and extracellular vesicles (EVs). Tumor-derived vesicles are known to have the ability to modulate the immune response. Monocytes are a subset of circulating innate immune cells and play a crucial role in immune surveillance, being recruited to tissues where they differentiate into macrophages. In the context of tumors, it has been observed that tumor cells can attract monocytes to the TME and induce their differentiation into tumor-associated macrophages with a pro-tumor phenotype. Tumor-derived EVs have emerged as essential structures mediating this process. Through the transfer of specific molecules and signaling factors, tumor-derived EVs can shape the phenotype and function of monocytes, inducing the expression of cytokines and molecules by these cells, thus modulating the TME towards an immunosuppressive environment.
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Vesículas Extracelulares , Macrófagos , Monocitos , Neoplasias , Microambiente Tumoral , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/fisiología , Humanos , Monocitos/inmunología , Microambiente Tumoral/inmunología , Neoplasias/inmunología , Neoplasias/patología , Macrófagos/inmunología , Citocinas , Diferenciación CelularRESUMEN
Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.
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Vacuna BCG , Inmunoterapia , Melanoma Experimental , Factor 88 de Diferenciación Mieloide , Transducción de Señal , Animales , Ratones , Vacuna BCG/inmunología , Vacuna BCG/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Inmunoterapia/métodos , Macrófagos/inmunología , Macrófagos/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium bovis/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Microambiente Tumoral/inmunologíaRESUMEN
Forkhead Box O1 (FOXO1) has been reported to play important roles in many tumors. However, FOXO1 has not been studied in pan-cancer. The purpose of this study was to reveal the roles of FOXO1 in pan-cancer (33 cancers in this study). Through multiple public platforms, a pan-cancer analysis of FOXO1 was conducted to obtained FOXO1 expression profiles in various tumors to explore the relationship between FOXO1 expression and prognosis of these tumors and to disclose the potential mechanism of FOXO1 in these tumors. FOXO1 was associated with the prognosis of multiple tumors, especially LGG (low grade glioma), OV (ovarian carcinoma), and KIRC (kidney renal clear cell carcinoma). FOXO1 might play the role of an oncogenic gene in LGG and OV, while playing the role of a cancer suppressor gene in KIRC. FOXO1 expression had a significant correlation with the infiltration of some immune cells in LGG, OV, and KIRC. By combining FOXO1 expression and immune cell infiltration, we found that FOXO1 might influence the overall survival of LGG through the infiltration of myeloid dendritic cells or CD4+ T cells. Functional enrichment analysis and gene set enrichment analysis showed that FOXO1 might play roles in tumors through immunoregulatory interactions between a lymphoid and a non-lymphoid cell, TGF-beta signaling pathway, and transcriptional misregulation in cancer. FOXO1 was associated with the prognosis of multiple tumors, especially LGG, OV, and KIRC. In these tumors, FOXO1 might play its role via the regulation of the immune microenvironment.
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Proteína Forkhead Box O1 , Neoplasias , Humanos , Biomarcadores de Tumor/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias/inmunología , Neoplasias/genética , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genéticaRESUMEN
Pituitary neuroendocrine tumors (PitNET) are known to be variably infiltrated by different immune cells. Nonetheless, their role in pituitary oncogenesis has only begun to be unveiled. The immune microenvironment could determine the biological and clinical behavior of a neoplasm and may have prognostic implications. To evaluate the expression of immune-related genes and to correlate such expression with the presence of infiltrating immune cells in forty-two PitNETs of different lineages, we performed whole transcriptome analysis and RT-qPCR. Deconvolution analysis was carried out to infer the immune cell types present in each tumor and the presence of immune cells was confirmed by immunofluorescence. We found characteristic expression profiles of immune-related genes including those encoding interleukins and chemokines for each tumor lineage. Genes such as IL4-I1, IL-36A, TIRAP, IL-17REL, and CCL5 were upregulated in all PitNETS, whereas IL34, IL20RA, and IL-2RB characterize the NR5A1-, TBX19-, and POU1F1-derived tumors, respectively. Transcriptome deconvolution analysis showed that M2 macrophages, CD4+ T cells, CD8+ T cells, NK cells, and neutrophils can potentially infiltrate PitNET. Furthermore, CD4+ and CD8+ T cells and NK cells infiltration was validated by immunofluorescence. Expression of CCL18, IL-5RA, and HLA-B as well as macrophage tumor infiltration could identify patients who can potentially benefit from treatment with immune checkpoint inhibitors.
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Tumores Neuroendocrinos , Neoplasias Hipofisarias , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/inmunología , Neoplasias Hipofisarias/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/patología , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica/métodos , Masculino , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , AdultoRESUMEN
The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.
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Linfocitos T CD4-Positivos , Homeostasis , Neoplasias , Animales , Humanos , Adaptación Fisiológica/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Homeostasis/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunologíaRESUMEN
Despite presenting a worse prognosis and being associated with highly aggressive tumors, triple-negative breast cancer (TNBC) is characterized by the higher frequency of tumor-infiltrating lymphocytes, which have been implicated in better overall survival and response to therapy. Though recent studies have reported the capacity of B lymphocytes to recognize overly-expressed normal proteins, and tumor-associated antigens, how tumor development potentially modifies B cell response is yet to be elucidated. Our findings reveal distinct effects of 4T1 and E0771 murine tumor development on B cells in secondary lymphoid organs. Notably, we observe a significant expansion of total B cells and plasma cells in the tumor-draining lymph nodes (tDLNs) as early as 7 days after tumor challenge in both murine models, whereas changes in the spleen are less pronounced. Surprisingly, within the tumor microenvironment (TME) of both models, we detect distinct B cell subpopulations, but tumor development does not appear to cause major alterations in their frequency over time. Furthermore, our investigation into B cell regulatory phenotypes highlights that the B10 Breg phenotype remains unaffected in the evaluated tissues. Most importantly, we identified an increase in CD19 + LAG-3 + cells in tDLNs of both murine models. Interestingly, although CD19 + LAG-3 + cells represent a minor subset of total B cells (< 3%) in all evaluated tissues, most of these cells exhibit elevated expression of IgD, suggesting that LAG-3 may serve as an activation marker for B cells. Corroborating with these findings, we detected distinct cell cycle and proliferation genes alongside LAG-3 analyzing scRNA-Seq data from a cohort of TNBC patients. More importantly, our study suggests that the presence of LAG-3 B cells in breast tumors could be associated with a good prognosis, as patients with higher levels of LAG-3 B cell transcripts had a longer progression-free interval (PFI). This novel insight could pave the way for targeted therapies that harness the unique properties of LAG-3 + B cells, potentially offering new avenues for improving patient outcomes in TNBC. Further research is warranted to unravel the mechanistic pathways of these cells and to validate their prognostic value in larger, diverse patient cohorts.
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Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Animales , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Femenino , Ratones , Microambiente Tumoral/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Línea Celular Tumoral , Proteína del Gen 3 de Activación de Linfocitos , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Antígenos CD/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Ganglios Linfáticos/patología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Ratones Endogámicos BALB CRESUMEN
INTRODUCTION: Triple negative breast cancer endophenotype (TNBC) is one of the least frequent and without therapeutic target; therefore we propose to study the correlation of PD-L1 immune checkpoint with the establishment of tumor microenvironment assessed by intratumoral stromal lymphocyte infiltration (TILS) and its importance in clinical practice. METHODS: A retrospective case-control study was performed, with 31 cases of triple-negative infiltrating breast carcinoma and 57 unmatched controls of Luminal A, Luminal B and HER-2 endophenotype seen in one year. The following variables were evaluated: histologic type and grade, PD-L1 expression with clone 22C3, TILS, lymphovascular invasion, tumor size, lymph node involvement and metastasis. Statistical analysis was performed with the chi-square test and Spearman correlation coefficient test. RESULTS: a statistically significant negative correlation was found between TILS and PD-L1 (rho - 0.106, p 0.025), indicating that the higher the expression of PD-L1, the lower the intratumoral lymphocytic infiltration. In the TILS B (10-40% TILS) and C (40-90% TILS) groups where there was a marked intratumoral inflammatory infiltrate, a greater number of patients were negative for PD-L1 (CPS <10) with 16 and 10 cases, respectively. For TNBC cases a negative association coefficient was identified (rho -0.378) with statistical significance (p 0.01). DISCUSSION: The association between TNBC, TILS and PDL1 expression was established, which is important for the establishment of target therapies and the development of precision medicine.
Introducción: El endofenotipo de cáncer de mama triple negativo (TNBC) es uno de los menos frecuentes y sin diana terapéutica, por tanto, se plantea estudiar la correlación del punto de control inmunológico PD-L1 con el establecimiento de microambiente tumoral evaluado por la infiltración linfocitaria intratumoral estromal (TILs) y su importancia en la práctica clínica. Métodos: Se realizó un estudio retrospectivo de casos y controles, con 31 casos de carcinoma infiltrante de la mama triple negativo y 57 controles no pareados de endofenotipo Luminal A, Luminal B y HER-2 atendidos en un año. Se evaluaron las variables: tipo y grado histológico, expresión PD-L1 con el clon 22C3, TILs, invasión linfovascular, tamaño tumoral, compromiso de ganglios linfáticos y metástasis. El análisis estadístico se ejecutó con la prueba de chi cuadrado y prueba de coeficiente de correlación de Spearman. Resultados: Se encontró una correlación negativa estadísticamente significativa entre TILs y PD-L1 (rho - 0.106, p 0.025), indicando que a mayor expresión de PD-L1, es menor la infiltración linfocitaria intratumoral. En los grupos de TILs B (10-40% TILs) y C (40-90% TILs) donde se presenta marcado infiltrado inflamatorio intratumoral se evidenció mayor número de pacientes negativos para PD-L1 (CPS <10) con 16 y 10 casos respectivamente. Para los casos TNBC se logró identificar un coeficiente de asociación negativa (rho -0.378) y con significancia estadística (p 0.01). Discusión: Se estableció la asociación de TNBC, TILs y expresión de PDL1, lo cual es importante para la instauración de terapias diana y el desarrollo de la medicina de precisión.
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Antígeno B7-H1 , Linfocitos Infiltrantes de Tumor , Neoplasias de la Mama Triple Negativas , Anciano , Femenino , Humanos , Persona de Mediana Edad , Antígeno B7-H1/análisis , Antígeno B7-H1/metabolismo , Estudios de Casos y Controles , Linfocitos Infiltrantes de Tumor/inmunología , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Interleukin (IL)-33 is an important cytokine in the tumour microenvironment; it is known to promote the growth and metastasis of solid cancers, such as gastric, colorectal, ovarian and breast cancer. Our group demonstrated that the IL-33/ST2 pathway enhances the development of squamous cell carcinoma (SCC). Conversely, other researchers have reported that IL-33 inhibits tumour progression. In addition, the crosstalk between IL-33, cancer cells and immune cells in SCC remains unknown. The aim of this study was to investigate the effect of IL-33 on the biology of head and neck SCC lines and to evaluate the impact of IL-33 neutralisation on the T cell response in a preclinical model of SCC. First, we identified epithelial and peritumoural cells as a major local source of IL-33 in human SCC samples. Next, in vitro experiments demonstrated that the addition of IL-33 significantly increased the proliferative index, motility and invasiveness of SCC-25 cells, and downregulated MYC gene expression in SCC cell lines. Finally, IL-33 blockade significantly delayed SCC growth and led to a marked decrease in the severity of skin lesions. Importantly, anti-IL-33 monoclonal antibody therapy increase the percentage of CD4+IFNγ+ T cells and decreased CD4+ and CD8+ T cells secreting IL-4 in tumour-draining lymph nodes. Together, these data suggest that the IL-33/ST2 pathway may be involved in the crosstalk between the tumour and immune cells by modulating the phenotype of head and neck SCC and T cell activity. IL-33 neutralisation may offer a novel therapeutic strategy for SCC.
Asunto(s)
Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Interleucina-33 , Activación de Linfocitos , Interleucina-33/metabolismo , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Animales , Activación de Linfocitos/inmunología , Invasividad Neoplásica , Ratones , Línea Celular Tumoral , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunología , FemeninoRESUMEN
BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.
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Proteínas de la Membrana , Neoplasias , Microambiente Tumoral , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN , Metilación de ADN , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Regulación Neoplásica de la Expresión Génica , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Inestabilidad de Microsatélites , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Pronóstico , Microambiente Tumoral/inmunologíaRESUMEN
Tumor is accompanied by complex and dynamic microenvironment development, and the interaction of all its components influences disease progression and response to treatment. Once the tumor microenvironment has been eradicated, various mechanisms can induce the tumors. Microorganisms can maintain the homeostasis of the tumor microenvironment through immune regulation, thereby inhibiting tumor development. Akkermania muciniphila (A. muciniphila), an anaerobic bacterium, can induce tumor immunity, regulate the gastrointestinal microenvironment through metabolites, outer membrane proteins, and some cytokines, and enhance the curative effect through combined immunization. Therefore, a comprehensive understanding of the complex interaction between A. muciniphila and human immunity will facilitate the development of immunotherapeutic strategies in the future and enable patients to obtain a more stable clinical response. This article reviews the most recent developments in the tumor immunity of A. muciniphila.
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Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Microambiente Tumoral/inmunología , Akkermansia/inmunología , Inmunoterapia/métodos , Microbioma Gastrointestinal/inmunología , Verrucomicrobia/inmunología , Citocinas/metabolismoRESUMEN
Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.
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Carcinoma de Células Renales , Interferón gamma , Neoplasias Renales , Células Asesinas Naturales , Macrófagos Asociados a Tumores , Células Asesinas Naturales/inmunología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Humanos , Animales , Ratones , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Progresión de la Enfermedad , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
CONTEXT: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. OBJECTIVE: Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). METHODS: We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.
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Células Madre Mesenquimatosas , Neoplasias Hipofisarias , Microambiente Tumoral , Humanos , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Microambiente Tumoral/inmunología , Neoplasias Hipofisarias/inmunología , Neoplasias Hipofisarias/patología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Adenoma/patología , Adenoma/inmunología , Adenoma/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/inmunología , Hipófisis/inmunología , Hipófisis/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
BACKGROUND: Neoadjuvant immunotherapy has evolved as an effective option to treat non-small cell lung cancer (NSCLC). B cells play essential roles in the immune system as well as cancer progression. However, the repertoire of B cells and its association with clinical outcomes remains unclear in NSCLC patients receiving neoadjuvant immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data for LUAD samples were accessed from the TCGA and GEO databases. LUAD-related B cell marker genes were confirmed based on comprehensive analysis of scRNA-seq data. We then constructed the B cell marker gene signature (BCMGS) and validated it. In addition, we evaluated the association of BCGMS with tumor immune microenvironment (TIME) characteristics. Furthermore, we validated the efficacy of BCGMS in a cohort of NSCLC patients receiving neoadjuvant immunotherapy. RESULTS: A BCMGS was constructed based on the TCGA cohort and further validated in three independent GSE cohorts. In addition, the BCMGS was proven to be significantly associated with TIME characteristics. Moreover, a relatively higher risk score indicated poor clinical outcomes and a worse immune response among NSCLC patients receiving neoadjuvant immunotherapy. CONCLUSIONS: We constructed an 18-gene prognostic signature derived from B cell marker genes based on scRNA-seq data, which had the potential to predict the prognosis and immune response of NSCLC patients receiving neoadjuvant immunotherapy.