RESUMEN
Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.
Asunto(s)
Neoplasias de la Mama , Senescencia Celular , Resistencia a Antineoplásicos , Células Madre Neoplásicas , Humanos , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Senescencia Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ingeniería Genética/métodos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Nanopartículas/química , Anticuerpos de Cadena Única/química , Escape del Tumor/efectos de los fármacos , Antígeno B7-H1/metabolismo , Apoptosis/efectos de los fármacos , Biomimética/métodos , Antígenos B7RESUMEN
The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti-EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC.
Asunto(s)
Neoplasias de Cabeza y Cuello , Inmunoterapia , Células Asesinas Naturales , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Células Asesinas Naturales/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/inmunología , Inmunoterapia/métodos , Animales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Escape del Tumor/efectos de los fármacos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Transducción de Señal , Cetuximab/uso terapéutico , Cetuximab/farmacologíaRESUMEN
Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
Asunto(s)
Biomarcadores de Tumor , Resistencia a Antineoplásicos , Evasión Inmune , Neoplasias , Células Madre Neoplásicas , Microambiente Tumoral , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/efectos de los fármacos , Humanos , Microambiente Tumoral/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Biomarcadores de Tumor/metabolismo , Animales , Escape del Tumor/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Células Escamosas , Resistencia a Antineoplásicos , Interleucina-8 , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Femenino , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Interleucina-8/genética , Interleucina-8/metabolismo , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genética , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer that is fatal and has a dismal prognosis. Obovatol (Ob), a novel lignan derived from the leaf and stem bark of Magnolia obovata Thunb, has exhibited anti-tumor effect on diverse tumors. However, its effect and mechanisms on HCC remain to be further explored. METHODS: Huh7 and Hep3B cells, as well as BALB/c nude mice were used to determine the function and mechanisms of Ob on growth, invasion and immune escape by cell counting kit-8, transwell, enzyme-linked immunosorbent assay (ELISA) and western blot experiments. RESULTS: Ob reduced the cell viability of Huh7 and Hep3B cells, with a IC50 value of 57.41 µM and 62.86 µM, respectively. Ob declined the invasion ability, the protein expression of N-cadherin and the concentrations of IL-10 and TGF-ß, whereas increased the E-cadherin expression and the contents of IFN-γ and IL-2 in Hep3B and Huh7 cells. Mechanically, Ob decreased the protein level of p-JAK/JAK, p-STAT3/STAT3 and PD-L1, which was partly restored with the treatment of RO8191, an activator of JAK/STAT3 axis. The effect of Ob on the cell viability, the invasion ability, the protein level of N-cadherin and E-cadherin, and the concentrations of IL-10, TGF-ß, IFN-γ and IL-2 in both Hep3B and Huh7 cells was reversed with the management of RO8191. In vivo, Ob reduced tumor volume and weight, the level of N-cadherin, PD-L1, p-JAK/JAK, and p-STAT3/STAT3, with an elevated expression of E-cadherin and IFN-γ. CONCLUSION: Ob downregulated the JAK/STST3/PD-L1 pathway to attenuate the growth, invasion and immune escape of HCC.
Asunto(s)
Antígeno B7-H1 , Carcinoma Hepatocelular , Proliferación Celular , Quinasas Janus , Neoplasias Hepáticas , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal , Humanos , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Quinasas Janus/metabolismo , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratones , Invasividad Neoplásica , Escape del Tumor/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Éteres Fenílicos/farmacología , Éteres Fenílicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Compuestos de BifeniloRESUMEN
Tumor cells engage with the immune system in a complex manner, utilizing evasion and adaptability mechanisms. The development of cancer and resistance to treatment relies on the ability of immune cells to adjust their phenotype and function in response to cues from the tumor microenvironment, known as immunological cell plasticity. This study delves into the role of long non-coding RNAs (lncRNAs) in enhancing immune cell flexibility in cancer, focusing on their regulatory actions in the tumor microenvironment and potential therapeutic implications. Through a comprehensive review of existing literature, the study analyzes the impact of lncRNAs on macrophages, T-cells, and MDSCs, as well as the influence of cytokines and growth factors like TNF, IL-6, HGF, and TGFß on immunological cell plasticity and tumor immunoediting. LncRNAs exert a strong influence on immune cell plasticity through mechanisms such as transcriptional regulation, post-transcriptional modifications, and chromatin remodeling. These RNA molecules intricately modulate gene expression networks, acting as scaffolding, decoys, guides, and sponges. Moreover, both direct cell-cell interactions and soluble chemicals in the tumor microenvironment contribute to enhancing immune cell activation and survival. Understanding the influence of lncRNAs on immune cell flexibility sheds light on the biological pathways of immune evasion and cancer progression. Targeting long non-coding RNAs holds promise for amplifying anti-tumor immunity and overcoming drug resistance in cancer treatment. However, further research is necessary to determine the therapeutic potential of manipulating lncRNAs in the tumor microenvironment.
Asunto(s)
Plasticidad de la Célula , Neoplasias , ARN Largo no Codificante , Microambiente Tumoral , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Microambiente Tumoral/inmunología , Animales , Plasticidad de la Célula/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Escape del Tumor/efectos de los fármacosRESUMEN
Bladder cancer is a highly prevalent malignancy. Asiaticoside (AC), a triterpenoid derivative, exhibits antitumor effect on different tumors. This study aimed to explore the role and mechanism of AC on bladder cancer. J82 and T24 cells were treated with AC and/or propofol, and nude mice were subcutaneously administrated with T24 cells. The effect and mechanism of AC and/or propofol were explored by cell counting kit-8, transwell, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry and western blot assays both in vitro and in vivo. Cell viability of J82 and T24 cells was inhibited by AC with a IC50 value of 2.43 µM and 2.16 µM, and by propofol with a IC50 value of 42.51 µM and 48.37 µM, respectively. AC or propofol alone decreased cell proliferation, invasion, and immune escape with the increased ferroptosis, as well as downregulating the level of the PI3K/AKT pathway in both animal and cell experiments. The effect of propofol on the above-mentioned indicators was further enhanced with the co-treatment of AC in vitro and in vivo. Taken together, AC promoted the ameliorative effect of propofol on bladder cancer involved in PI3K/AKT pathway.
Asunto(s)
Ferroptosis , Ratones Desnudos , Propofol , Triterpenos , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inmunología , Animales , Triterpenos/farmacología , Humanos , Propofol/farmacología , Ferroptosis/efectos de los fármacos , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Invasividad Neoplásica , Escape del Tumor/efectos de los fármacos , Sinergismo Farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.
Asunto(s)
Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Evasión Inmune , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Ratones Endogámicos C57BL , Escape del Tumor/efectos de los fármacosRESUMEN
BACKGROUND: Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. METHODS: The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. RESULTS: APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. CONCLUSIONS: APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.
Asunto(s)
Antígeno B7-H1 , Melanoma Experimental , Células Madre Neoplásicas , Polisacáridos , Antígeno B7-H1/metabolismo , Animales , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Ratones , Polisacáridos/farmacología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Escape del Tumor/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Humanos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Melanoma/inmunología , Planta del Astrágalo/química , Evasión InmuneRESUMEN
Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but has shown limited efficacy in gynecologic cancers. VISTA (V-domain Ig suppressor of T-cell activation), a member of the B7 family, is emerging as another checkpoint that regulates the anti-tumor immune responses within the tumor microenvironment. This paper reviews the structure, expression, and mechanism of action of VISTA. Furthermore, it highlights recent advances in VISTA-blocking therapies and their potential in improving outcomes for patients with gynecologic cancers. By understanding the role of VISTA in mediating the immune evasion of gynecologic tumors, we can develop more effective combinatory treatment strategies that could overcome resistance to current ICB therapies.
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Antígenos B7 , Neoplasias de los Genitales Femeninos , Inhibidores de Puntos de Control Inmunológico , Escape del Tumor , Microambiente Tumoral , Humanos , Neoplasias de los Genitales Femeninos/inmunología , Femenino , Antígenos B7/inmunología , Antígenos B7/metabolismo , Microambiente Tumoral/inmunología , Escape del Tumor/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Animales , Inmunoterapia/métodosRESUMEN
Tumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion. Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME). There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC.
Asunto(s)
Linfocitos T CD8-positivos , Colesterol , Neoplasias Colorrectales , Fosfatasas de Especificidad Dual , Animales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Ratones , Humanos , Colesterol/biosíntesis , Colesterol/metabolismo , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de Especificidad Dual/antagonistas & inhibidores , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genética , FemeninoRESUMEN
Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; collectively, they constitute a significant portion of the tumor microenvironment (TME) in CCA. By secreting cytokines and other chemicals, regulatory T cells (Tregs) decrease activated T cell responses, acting as immunosuppressors. Reduced CD8+ T cell activation results in stimulating programmed death-1 (PD-1), which undermines the immunological homeostasis of T lymphocytes. On the other hand, cancer cells are eliminated by activated cytotoxic T lymphocyte (CTL) through the perforin-granzyme or Fas-FasL pathways. Th1 and CTL immune cell infiltration into the malignant tumor is also facilitated by γδ T cells. A higher prognosis is typically implied by CD8+ T cell infiltration, and survival is inversely associated with Treg cell density. Immune checkpoint inhibitors, either singly or in combination, provide novel therapeutic strategies for CCA immunotherapy. Furthermore, it is anticipated that immunotherapeutic strategies-such as the identification of new immune targets, combination treatments involving several immune checkpoint inhibitors, and chimeric antigen receptor-T therapies (CAR-T)-will optimize the effectiveness of anti-CCA treatments while reducing adverse effects.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Escape del Tumor , Microambiente Tumoral , Humanos , Colangiocarcinoma/inmunología , Colangiocarcinoma/terapia , Colangiocarcinoma/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/terapia , Neoplasias de los Conductos Biliares/patología , Microambiente Tumoral/inmunología , Inmunoterapia/métodos , Escape del Tumor/efectos de los fármacos , Escape del Tumor/inmunología , Animales , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos T Reguladores/inmunologíaRESUMEN
The interaction between the immune system and the tumor matrix has a huge impact on the progression and treatment of cancer. This paper summarizes and discusses the crosstalk between T cells and cancer-associated fibroblasts (CAFs). CAFs can also produce inhibitors that counteract the function of T cells and promote tumor immune escape, while T cells can also engage in complex two-way interactions with CAFs through direct cell contact, the exchange of soluble factors such as cytokines, and the remodeling of the extracellular matrix. Precise targeted intervention can effectively reverse tumor-promoting crosstalk between T cells and CAFs, improve anti-tumor immune response, and provide a new perspective for cancer treatment. Therefore, it is important to deeply understand the mechanism of crosstalk between T cells and CAFs. This review aims to outline the underlying mechanisms of these interactions and discuss potential therapeutic strategies that may become fundamental tools in the treatment of cancer, especially hard-to-cure cancers.
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Fibroblastos Asociados al Cáncer , Neoplasias , Linfocitos T , Microambiente Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Animales , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Comunicación Celular , Escape del Tumor/efectos de los fármacos , Citocinas/metabolismo , Citocinas/inmunología , Matriz Extracelular/metabolismoRESUMEN
Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.
Asunto(s)
Antígenos CD36 , Decitabina , Leucemia Mieloide Aguda , Metabolismo de los Lípidos , Lipoproteínas LDL , Antígenos CD36/metabolismo , Antígenos CD36/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Metabolismo de los Lípidos/efectos de los fármacos , Decitabina/farmacología , Decitabina/uso terapéutico , Lipoproteínas LDL/metabolismo , Animales , FN-kappa B/metabolismo , Línea Celular Tumoral , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Ratones , Transducción de Señal/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Aciltransferasas/genética , Inmunidad Innata/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular carcinoma (HCC), with only a small percentage of patients responding positively to treatment. The mechanism underlying resistance to ICT in HCC remains poorly understood. Here, we showed that combination treatment of ICG-001, an inhibitor of the Wnt/ß-catenin signaling pathway, with anti-PD-1 antibody effectively suppresses tumor growth and promotes the infiltration of immune cells such as DCs and CD8+ T cells in the tumor microenvironment (TME). By inhibiting the activity of ß-catenin and blocking its binding to the transcription factor IKAROS family zinc finger 1 (IKZF1), ICG-001 upregulated the expression of CCL5. Moreover, IKZF1 regulated the activity of the CCL5 promoter and its endogenous expression. Through inhibition of the WNT/ß-catenin signaling pathway, upregulation of the expression of CCL5 was achieved, which subsequently recruited more DCs into the TME via C-C motif chemokine receptor 5 (CCR5). This, in turn, resulted in an increase in the infiltration of CD8+ T cells in the TME, thereby enhancing the antitumor immune response. Analysis of a tissue microarray derived from HCC patient samples revealed a positive correlation between survival rate and prognosis and the expression levels of CCL5/CD8. In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/ß-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.
Asunto(s)
Carcinoma Hepatocelular , Quimiocina CCL5 , Neoplasias Hepáticas , Vía de Señalización Wnt , beta Catenina , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Humanos , Animales , Vía de Señalización Wnt/efectos de los fármacos , Quimiocina CCL5/metabolismo , beta Catenina/metabolismo , Ratones , Línea Celular Tumoral , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Factor de Transcripción Ikaros/metabolismo , Factor de Transcripción Ikaros/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Benzodioxoles/farmacología , Benzodioxoles/uso terapéutico , Escape del Tumor/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Evasión Inmune , Compuestos Bicíclicos Heterocíclicos con PuentesRESUMEN
OBJECTIVES: We aimed to explore the effects and mechanisms of action of dehydroepiandrosterone (DHEA) on immune evasion of oral squamous cell carcinoma (OSCC) to provide evidence for enhancing the effect of immunotherapy. MATERIALS AND METHODS: A xenograft mouse model and immunohistochemistry were used to reveal the patterns of tumor-infiltrating lymphocytes (TILs). The CAL27 and SCC VII cell lines were used for the in vitro study. Western blotting, qPCR, immunofluorescence, and flow cytometry were used to evaluate the expression of B7-H4. Recombinant mouse B7-H4 protein (rmB7-H4) and PG490, an inhibitor of NF-κB p65 were used for the "rescue study." Gain- and loss-of-function, luciferase reporter, and chromatin immunoprecipitation assays were performed to verify this mechanism. RESULTS: DHEA inhibited tumor growth in an OSCC xenograft mouse model, increased CD8 + cells, and decreased FOXP3 + cells in TILs. DHEA reduced the expression of B7-H4 in CAL27 and SCC VII cells RmB7-H4 reverses the effect of DHEA on tumor growth and TIL patterns. DHEA increased the expression of miR-15b-5p and activated its transcriptional factor NF-κB p65. Further experiments demonstrated that miR-15b-5p inhibited B7-H4 expression by binding to its 3'-UTR regions, and NF-κB p65 activated miR-15b transcription. PG490 reversed the effects of DHEA on tumor growth, antitumor immunity in the OSCC xenograft model, and the expression/phosphorylation of NF-κB p65, miR-15b-5p, and B7-H4. CONCLUSIONS: This study indicates that DHEA attenuates the immune escape of OSCC cells by inhibiting B7-H4 expression, providing new insights for cancer immunotherapy.
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Carcinoma de Células Escamosas , Deshidroepiandrosterona , MicroARNs , Neoplasias de la Boca , Factor de Transcripción ReIA , Escape del Tumor , Inhibidor 1 de la Activación de Células T con Dominio V-Set , Animales , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/tratamiento farmacológico , Humanos , Factor de Transcripción ReIA/metabolismo , Deshidroepiandrosterona/farmacología , Deshidroepiandrosterona/uso terapéutico , Escape del Tumor/efectos de los fármacos , Línea Celular Tumoral , Inhibidor 1 de la Activación de Células T con Dominio V-Set/genética , Inhibidor 1 de la Activación de Células T con Dominio V-Set/metabolismo , Ratones , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
BACKGROUND: APLNR is a G protein-coupled receptor and our previous study had revealed that APLNR could inhibit nasopharyngeal carcinoma (NPC) growth and metastasis. However, the role of APLNR in regulating PD-L1 expression and immune escape in NPC is unknown. METHODS: We analyzed the expression and correlation of APLNR and PD-L1 in NPC tissues and cells. We investigated the effect of APLNR on PD-L1 expression and the underlying mechanism in vitro and in vivo. We also evaluated the therapeutic potential of targeting APLNR in combination with PD-L1 antibody in a nude mouse xenograft model. RESULTS: We found that APLNR was negatively correlated with PD-L1 in NPC tissues and cells. APLNR could inhibit PD-L1 expression by binding to the FERM domain of JAK1 and blocking the interaction between JAK1 and IFNGR1, thus suppressing IFN-γ-mediated activation of the JAK1/STAT1 pathway. APLNR could also inhibit NPC immune escape by enhancing IFN-γ secretion and CD8+ T-cell infiltration and reducing CD8+ T-cell apoptosis and dysfunction. Moreover, the best effect was achieved in inhibiting NPC growth in nude mice when APLNR combined with PD-L1 antibody. CONCLUSIONS: Our study revealed a novel mechanism of APLNR regulating PD-L1 expression and immune escape in NPC and suggested that APLNR maybe a potential therapeutic target for NPC immunotherapy.
Asunto(s)
Antígeno B7-H1 , Ratones Desnudos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Escape del Tumor , Animales , Femenino , Humanos , Masculino , Ratones , Antígeno B7-H1/metabolismo , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interferón gamma/metabolismo , Janus Quinasa 1/metabolismo , Ratones Endogámicos BALB C , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/patología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología , Receptores de Interferón/genética , Receptores de Interferón/metabolismo , Factor de Transcripción STAT1/metabolismo , Escape del Tumor/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. MAIN BODY: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. CONCLUSION: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.
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Epigénesis Genética , Neoplasias Gastrointestinales , Complejo Mayor de Histocompatibilidad , Humanos , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/inmunología , Epigénesis Genética/genética , Complejo Mayor de Histocompatibilidad/genética , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos , Metilación de ADN/genética , Escape del Tumor/genética , Escape del Tumor/efectos de los fármacosRESUMEN
Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa , Interferón gamma , Quinurenina , Proteína Proto-Oncogénica c-fli-1 , Factor de Transcripción STAT1 , Linfocitos T Reguladores , Microambiente Tumoral , Quinurenina/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Animales , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Humanos , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Factor de Transcripción STAT1/metabolismo , Línea Celular Tumoral , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/tratamiento farmacológico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones Endogámicos C57BL , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Ratones NoqueadosRESUMEN
Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond-there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3ß, cytokines IFN-γ and IL-1ß, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response-addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone.