RESUMEN
BACKGROUND: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge. METHODS: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed. RESULTS: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17. CONCLUSION: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.
Asunto(s)
Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Microambiente Tumoral/inmunología , Masculino , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Anciano de 80 o más Años , Pronóstico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismoRESUMEN
OBJECTIVE: To understand the CD8+ tumour infiltrating lymphocyte (TIL) compartment of oesophageal adenocarcinoma (OAC) with regards to markers of lymphocyte exhaustion, tissue residency and to identify possible reasons behind differential responses to therapy. DESIGN: Tumour samples from 44 patients undergoing curative resection for OAC were assessed by flow cytometry for presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of PD-1 and CD39 positive OAC TILs were sorted, and bulk RNA sequencing undertaken using a modified SmartSeq2 protocol. Flow cytometric assessment of functionality was completed. RESULTS: A higher proportion of antigen experienced CD8+ OAC TILs was associated with improved survival following surgery; while, high double positivity (DP) for PD-1 and CD39 among these TILs also correlated significantly with outcome. These DP TILs possess a minority population which is positive for the markers of exhaustion TIM3 and LAG3. Transcriptomic assessment of the PD-1 and CD39 DP TILs demonstrated enrichment for a tissue resident memory T lymphocyte (TRM) phenotype associated with improved survival in other cancers, reinforced by positivity for the canonical TRM marker CD103 by flow cytometry. This population demonstrated maintained functional capacity both in their transcriptomic profile, and on flow cytometric assessment, as well as preserved proliferative capacity. CONCLUSION: Resected OAC are variably infiltrated by PD-1 and CD39 DP TILs, an abundance of which among lymphocytes is associated with improved survival. This DP population has an increased, but still modest, frequency of TIM3 and LAG3 positivity compared to DN, and is in keeping with a functionally competent TRM phenotype.
Asunto(s)
Adenocarcinoma , Antígenos CD , Apirasa , Linfocitos T CD8-positivos , Neoplasias Esofágicas , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Receptor de Muerte Celular Programada 1/metabolismo , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Apirasa/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Masculino , Femenino , Antígenos CD/metabolismo , Persona de Mediana Edad , Anciano , Pronóstico , Biomarcadores de Tumor , Cadenas alfa de Integrinas/metabolismoRESUMEN
Tumor cell-originated events prevent efficient antitumor immune response and limit the application of anti-PD1 checkpoint immunotherapy. We show that syndecan-1 (SDC1) has a critical role in the regulation of T cell-mediated control of tumor growth. SDC1 inhibition increases the permeation of CD8+ T cells into tumors and triggers CD8+ T cell-mediated control of tumor growth, accompanied by increased proportions of progenitor-exhausted and effector-like CD8+ T cells. SDC1 deficiency alters multiple signaling events in tumor cells, including enhanced IFN-γ-STAT1 signaling, and augments antigen presentation and sensitivity to T cell-mediated cytotoxicity. Combinatory inhibition of SDC1 markedly potentiates the therapeutic effects of anti-PD1 in inhibiting tumor growth. Consistently, the findings are supported by the data from human tumors showing that SDC1 expression negatively correlates with T cell presence in tumor tissues and the response to immune checkpoint blockade therapy. Our findings suggest that SDC1 inhibits antitumor immunity, and that targeting SDC1 may promote anti-PD1 response for cancer treatment.
Asunto(s)
Linfocitos T CD8-positivos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Sindecano-1 , Sindecano-1/metabolismo , Animales , Ratones , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Humanos , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/patología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T-cell activation to elucidate the Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with T-cell receptor microcluster (TCR-MC) upon T-cell activation similar to PD-1. Lag-3 blocking antibodies (Abs) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation. Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab, which did not block MHC-II binding could still block Lag-3's inhibitory function, suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T-cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T-cell activation at TCR-MC, and the target of Lag-3 ICI is to dissociate the co-localization of Lag-3 with TCR-MC.
Asunto(s)
Antígenos CD , Inhibidores de Puntos de Control Inmunológico , Proteína del Gen 3 de Activación de Linfocitos , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Antígenos CD/inmunología , Antígenos CD/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , AnimalesRESUMEN
With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti-PD-1/PD-L1 axis therapy. Anti-PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-ß, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti-PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti-PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti-PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas de la Membrana , Receptor de Muerte Celular Programada 1 , Transducción de Señal , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Animales , Proteínas de la Membrana/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Transducción de Señal/efectos de los fármacos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ratones , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Línea Celular Tumoral , Fosforilación , FemeninoRESUMEN
Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.
Asunto(s)
Antígeno B7-H1 , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Neoplasias Urológicas , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Inmunoterapia/métodos , Neoplasias Urológicas/terapia , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/inmunología , Neoplasias Urológicas/etiología , Neoplasias Urológicas/patología , Animales , Transducción de Señal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Escape del TumorRESUMEN
Prostate cancer presents as an immunologically "cold" malignancy, characterized by a lack of response to immunotherapy in the majority of patients. The dysfunction of prostate tumor metabolism is recognized as a critical factor in immune evasion, resulting in reduced effectiveness of immunotherapeutic interventions. Despite this awareness, the precise molecular mechanisms underpinning metabolic dysregulation in prostate cancer and its intricate relationship with immune evasion remain incompletely elucidated. In this study, we introduce the multi-drug resistance protein ABCC4/MRP4 as a key player prominently expressed in prostate cancer, exerting a pivotal role in suppressing the activity of intratumoral CD8+ T cells. Depletion of ABCC4 in prostate cancer cells halts the release of prostaglandin E2 (PGE2), a molecule that diminishes the population of CD8+ T cells and curtails their cytotoxic capabilities. Conversely, constraining the activation of PGE2 signaling in CD8+ T cells effectively improved the efficacy of prostate cancer treatment with PD-1 blockade. During this process, downregulation of the JAK1-STAT3 pathway and depolarization of mitochondria emerge as crucial factors contributing to T cell anergy. Collectively, our research identifies the ABCC4-PGE2 axis as a promising target for reversing dysfunction within tumor-infiltrating lymphocytes (TILs) and augmenting the suboptimal responsiveness to immunotherapy in prostate cancer.
Asunto(s)
Linfocitos T CD8-positivos , Dinoprostona , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias de la Próstata , Masculino , Neoplasias de la Próstata/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Dinoprostona/metabolismo , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Línea Celular Tumoral , Animales , RatonesRESUMEN
This study aimed to determine the effect of ozone on the expression of Bax and Bcl-2 genes in dental pulp cells. Additionally, the programmed cell death protein 1, programmed death-ligand 1, and CD200 antigens were determined in lymphocytes to assess their surface expression. Dental pulp cells were cultured from extracted healthy third molars and characterized as dental pulp stromal cells. Gene expression of Bcl-2 and Bax was analyzed at 0 s, 6 s, and 12 s of ozone exposure using real-time PCR. Lymphocytes from dental pulp were subjected to ozone exposure for 12 s and PD-1, PD-L1, and CD200/CD200R expression was analyzed by flow cytometry. Upon exposure to ozone for 6 s, the Bcl-2 expression decreased significantly to -0.09, and at 12 s, it increased significantly to 0.3. Bax gene expression level increased significantly to 0.188 after 6 s exposure, and at 12 s, to 0.16. Lymphocytes exposed to ozone for 12 s showed minimal changes in PD-1, PD-L1, and CD200/CD200R expression levels, indicating that oxidative stress does not impact the signaling pathways regulating these molecules. The significant upregulation of Bcl-2 at 12 s highlights the cells' effort to protect themselves from prolonged oxidative stress, possibly tipping the balance toward cell survival and tissue repair. However, the absence of changes in PD-1 and PD-L1 expression on lymphocytes under oxidative stress suggests that these molecules are not sensitive to oxidative stress in this context.
Asunto(s)
Antígenos CD , Apoptosis , Antígeno B7-H1 , Pulpa Dental , Ozono , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Pulpa Dental/citología , Pulpa Dental/metabolismo , Apoptosis/efectos de los fármacos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Células Cultivadas , Estrés Oxidativo , Proyectos Piloto , Regulación de la Expresión Génica/efectos de los fármacos , Linfocitos/metabolismo , Linfocitos/inmunología , Linfocitos/efectos de los fármacos , Adulto Joven , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Adulto , Transducción de Señal/efectos de los fármacosRESUMEN
Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.
Asunto(s)
Antígeno B7-H1 , Resistencia a Antineoplásicos , Proteómica , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteómica/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Masculino , Transcriptoma , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear. METHODS: Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy. RESULTS: We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR-661 and miR-671-5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD-1 therapy. CONCLUSIONS: Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.
Asunto(s)
Linfocitos T CD8-positivos , Vesículas Extracelulares , ARN Circular , Neoplasias Gástricas , Neoplasias Gástricas/patología , Neoplasias Gástricas/inmunología , ARN Circular/genética , Humanos , Vesículas Extracelulares/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Progresión de la Enfermedad , Ratones Desnudos , Resistencia a Antineoplásicos , Proliferación Celular/efectos de los fármacos , Femenino , Ratones Endogámicos BALB C , Masculino , Inhibidores de Puntos de Control Inmunológico/farmacología , Agotamiento de Células TRESUMEN
Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan-Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003-0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011-0.260; p < 0.0001). The Kaplan-Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071-0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05-0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2-3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5-9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Proteómica , Transcriptoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Melanoma/mortalidad , Femenino , Masculino , Estudios Retrospectivos , Proteómica/métodos , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Biomarcadores de Tumor/genética , Adulto , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/metabolismo , Metástasis de la NeoplasiaRESUMEN
Due to the genetic diversity between the mother and the fetus, heightened control over the immune system during pregnancy is crucial. Immunological parameters determined by clinicians in women with idiopathic recurrent spontaneous abortion (RSA) include the quantity and activity of Natural Killer (NK) and Natural Killer T (NKT) cells, the quantity of regulatory T lymphocytes, and the ratio of pro-inflammatory cytokines, which indicate imbalances in Th1 and Th2 cell response. The processes are controlled by immune checkpoint proteins (ICPs) expressed on the surface of immune cells. We aim to investigate differences in the expression of ICPs on T cells, T regulatory lymphocytes, NK cells, and NKT cells in peripheral blood samples collected from RSA women, pregnant women, and healthy multiparous women. We aim to discover new insights into the role of ICPs involved in recurrent pregnancy loss. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from blood samples obtained from 10 multiparous women, 20 pregnant women (11-14th week of pregnancy), and 20 RSA women, at maximum of 72 h after miscarriage. The PBMCs were stained for flow cytometry analysis. Standard flow cytometry immunophenotyping of PBMCs was performed using antibodies against classical lymphocyte markers, including CD3, CD4, CD8, CD56, CD25, and CD127. Additionally, ICPs were investigated using antibodies against Programmed Death Protein-1 (PD-1, CD279), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3, CD366), V-domain Ig suppressor of T cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT), and Lymphocyte activation gene 3 (LAG-3). We observed differences in the surface expression of ICPs in the analyzed subpopulations of lymphocytes between early pregnancy and RSA, after miscarriage, and in women. We noted diminished expression of PD-1 on T lymphocytes (p = 0.0046), T helper cells (CD3CD4 positive cells, p = 0.0165), T cytotoxic cells (CD3CD8 positive cells, p = 0.0046), T regulatory lymphocytes (CD3CD4CD25CD127 low positive cells, p = 0.0106), and NKT cells (CD3CD56/CD16 positive cells, p = 0.0438), as well as LAG-3 on lymphocytes T (p = 0.0225) T helper, p = 0.0426), T cytotoxic cells (p = 0.0458) and Treg (p = 0.0293), and cells from RSA women. Impaired expression of TIM-3 (p = 0.0226) and VISTA (p = 0.0039) on CD8 cytotoxic T and NK (TIM3 p = 0.0482; VISTA p = 0.0118) cells was shown, with an accompanying increased expression of TIGIT (p = 0.0211) on NKT cells. The changes in the expression of surface immune checkpoints indicate their involvement in the regulation of pregnancy. The data might be utilized to develop specific therapies for RSA women based on the modulation of ICP expression.
Asunto(s)
Aborto Habitual , Biomarcadores , Proteínas de Punto de Control Inmunitario , Células Asesinas Naturales , Humanos , Femenino , Embarazo , Aborto Habitual/inmunología , Aborto Habitual/metabolismo , Aborto Habitual/sangre , Adulto , Biomarcadores/sangre , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas de Punto de Control Inmunitario/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Inmunofenotipificación , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Antígenos CD/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
Immune checkpoint blockades are actively adopted in diverse cancer types including metastatic melanoma and lung cancer. Despite of durable response in 20-30% of patients, we still lack molecular markers that could predict the patient responses reliably before treatment. Here we present a composite model for predicting anti-PD-1 response based on tumor mutation burden (TMB) and transcriptome sequencing data of 85 lung adenocarcinoma (LUAD) patients who received anti-PD-(L)1 treatment. We found that TMB was a good predictor (AUC = 0.81) for PD-L1 negative patients (n = 20). For PD-L1 positive patients (n = 65), we built an ensemble model of 100 XGBoost learning machines where gene expression, gene set activities and cell type composition were used as input features. The transcriptome-based models showed excellent accuracy (AUC > 0.9) and highlighted the contribution of T cell activities. Importantly, nonresponder patients with high prediction score turned out to have high CTLA4 expression, which suggested that neoadjuvant CTLA4 combination therapy might be effective for these patients. Our data and analysis results provide valuable insights into developing biomarkers and strategies for treating LUAD patients using immune checkpoint inhibitors.
Asunto(s)
Adenocarcinoma del Pulmón , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Transcriptoma , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Biomarcadores de Tumor/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Mutación , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Perfilación de la Expresión Génica/métodosAsunto(s)
Linfoma de Células T Periférico , Receptor de Muerte Celular Programada 1 , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patología , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Pronóstico , Linfadenopatía Inmunoblástica/patología , Linfadenopatía Inmunoblástica/metabolismo , Linfadenopatía Inmunoblástica/diagnóstico , Biomarcadores de Tumor/metabolismoRESUMEN
Skin cancer is a widespread worldwide health concern, manifesting in many subtypes such as squamous cell carcinoma, basal cell carcinoma, and melanoma. Although all these types occur frequently, they generally lack the possibility of being cured, emphasizing the importance of early discovery and treatment. This comprehensive study explores the role of programmed cell death protein 1 (PD-1) in skin cancer, focusing on its molecular mechanisms in immune regulation and its critical role in tumor immune evasion, while also clarifying the complexities of immune checkpoints in cancer pathogenesis. It critically evaluates the clinical applications of PD-1 inhibitors, spotlighting their therapeutic potential in treating skin cancer, while also addressing the significant challenge of resistance. This work further discusses the evolution of resistance mechanisms against PD-1 inhibitors and suggests potential approaches to mitigate these issues, thereby enhancing the effectiveness of these therapies. The study further highlights the current state of PD-1 targeted therapies and sets the stage for future research aimed at optimizing these treatments for better clinical outcomes in skin cancer.
Asunto(s)
Resistencia a Antineoplásicos , Receptor de Muerte Celular Programada 1 , Neoplasias Cutáneas , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
The diagnosis of Sézary syndrome (SS) relies on the identification of blood Sézary cells (SC) by different markers via flow cytometry. Treatment of SS is challenging since its pathogenesis is characterized by cell death resistance rather than hyperproliferation. In this study, we establish an integrated approach that considers both the expression of SC markers and sensitivity to cell death both spontaneously and upon in vitro treatment. Peripheral blood mononuclear cells were isolated from 20 SS patients and analysed for the SC markers CD7 and CD26 loss as well as CD158k and PD1 gain. The cells were then treated with different established and experimental therapies in vitro and cell death was measured. Spontaneous and therapeutically induced cell death were measured and correlated to cellular marker profiles. In the marker-positive cells, spontaneous cell death sensitivity was reduced. Different treatments in vitro managed to specifically induce cell death in the putative CTCL cell populations. Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.
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Biomarcadores de Tumor , Muerte Celular , Citometría de Flujo , Síndrome de Sézary , Neoplasias Cutáneas , Síndrome de Sézary/metabolismo , Humanos , Biomarcadores de Tumor/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Dipeptidil Peptidasa 4/metabolismo , Femenino , Persona de Mediana Edad , Anciano , Masculino , Leucocitos Mononucleares/metabolismo , Antígenos CD7/metabolismo , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
BACKGROUND: Cervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic agents, but their efficacy when combined with neoadjuvant chemotherapy (NACT) has not been fully tested, and how they alter the tumor microenvironment has not been comprehensively elucidated. METHODS: In this study, we conducted single-cell RNA sequencing using 46,950 cells from nine human cervical cancer tissues representing sequential different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and identified the crucial factors involved in combination therapy. Cell-cell communication analysis was performed between tumor and immune cells. In addition, THP-1-derived and primary monocyte-derived macrophages were cocultured with cervical cancer cells and phagocytosis was detected by flow cytometry. The antitumor activity of blocking CD74 was validated in vivo using a CD74 humanized subcutaneous tumor model. RESULTS: Pathway enrichment analysis indicated that NACT activated cytokine and complement-related immune responses. Cell-cell communication analysis revealed that after NACT therapy, interaction strength between T cells and cancer cells decreased, but intensified between macrophages and cancer cells. We verified that macrophages were necessary for the PD-1 blockade to exert antitumor effects in vitro. Additionally, CD74-positive macrophages frequently interacted with the most immunoreactive epithelial subgroup 3 (Epi3) cancer subgroup during combination NACT. We found that CD74 upregulation limited phagocytosis and stimulated M2 polarization, whereas CD74 blockade enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vitro and in vivo. CONCLUSIONS: Our study reveals the dynamic cell-cell interaction network in the cervical cancer microenvironment influenced by combining NACT and PD-1 blockade. Furthermore, blocking tumor-associated macrophage-derived CD74 could augment neoadjuvant therapeutic efficacy.
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Inhibidores de Puntos de Control Inmunológico , Terapia Neoadyuvante , Macrófagos Asociados a Tumores , Neoplasias del Cuello Uterino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Humanos , Femenino , Terapia Neoadyuvante/métodos , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Ratones , Animales , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente Tumoral , Antígenos de Diferenciación de Linfocitos B/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos de Histocompatibilidad Clase IIRESUMEN
OBJECTIVE: To investigate the expression and significance of PD-1/PD-L1 in MDS blast cells, T lymphocyte cell subsets and Treg cells. METHODS: Eighty-eight MDS patients and 19 AML patients were collectd as the study subjects, and Iron deficiency anemia and healthy bone marrow donors were used as control group. The expression of PD-1/PD-L1 in MDS/AML blast cells, T lymphocyte cell subsets and Treg cells was detected by flow cytometry, and the expression level of Th1/Th2/Th17-related cytokines in peripheral serum was detected. RESULTS: The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells in low risk MDS group were lower than that in control group, medium and high risk MDS group and AML groupï¼all P < 0.01ï¼, and Th1/Th17 type cytokines were dominant. The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells of intermediate and high risk MDS group and AML group were higher than that of control group and low risk MDS group (all P < 0.01), and Th2 type and Treg type (IL-10ãTGF-ß) cytokines were dominant. After treatment, the differences of PD-1/PD-L1 expression were not statisticatly significant in blast cells, T lymphocyte cell subsets and Treg cells between the MDS remission group and the control group (all P >0.05). The expression of PD-1/PD-L1 in blast cells, T lymphocyte cell subsets and Treg cells in MDS non-remission group were significantly higher than that in remission group and control group (all P < 0.01). CONCLUSION: The high expression of PD-1/PD-L1, dominance of Treg (IL-10ãTGF-ß) and Th2-related cytokines and inhibition of effector T lymphocyte cells in patients with MDS is conducive to tumor cell proliferation and immune escape, which may promote the progression of MDS disease.
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Antígeno B7-H1 , Síndromes Mielodisplásicos , Receptor de Muerte Celular Programada 1 , Subgrupos de Linfocitos T , Linfocitos T Reguladores , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Síndromes Mielodisplásicos/metabolismo , Leucemia Mieloide Aguda , Citocinas/metabolismo , Interleucina-10/metabolismo , Células Th17RESUMEN
OBJECTIVE: The aim of this study was to assess the prognostic significance of α-1,3-mannitrotransferase (ALG3) in triple-negative breast cancer (TNBC) and investigate its impact and potential mechanism on the efficacy of anti-PD-1 therapy. METHODS: Bioinformatics analysis was used to examine the expression of ALG3 in cancer patients using UACLAN and other databases. The associations of the ALG3 gene and the clinicopathological features of breast cancer were examined with bc-GenExMiner database. Correlation between ALG3 expression and survival was further established utilizing the Kaplan-Meier Plotter database. Immunohistochemistry (IHC) was used to analyze the expression of ALG3 in cohort of breast cancer patients from Hubei cancer hospital to confirmed the prognostic value of ALG3 in TNBC. The effect of ALG3 on the levels of infiltrating immune cells was also analyzed. And the mutation module within cBioPortal was utilized to visualize ALG3 mutations in BRCA. The CRISPR/Cas9 technique was used to establish ALG3 low-expression TNBC cell lines. Influence of ALG3 expression on cancer cell proliferation and chemotherapeutic responsiveness was scrutinized in vitro. Animal models were constructed to evaluate the alteration of tumor sensitivity to anti-PD-1 therapy with decreased ALG3 expression. And flow cytometry and IHC were used to investigate the tumor immune microenvironment. Association of PD-L1 Glycosylation and ALG3 expression were also investigated by western blot. RESULTS: ALG3 expression was elevated in TNBC and was strikingly linked to unfavorable clinical features such as lymphatic node metastasis, high NPI, advanced stage and age, etc. Furthermore, high ALG3 expression was associated with shorter OS in TNBC patients. Mechanistically, ALG3 expression was negatively correlated with the infiltration of CD8+ T cells, CD4+ T cells, and NK cells. ALG3-KO cells had increased sensitivity to chemotherapeutic agents. In animal models, the volume of ALG3-KO tumors was lower than the control group with immunotherapy. ALG3-KO tumors showed an increased proportion of CD8+ T cells, while a decreased proportion of regulatory T cells and M2-type macrophages. The expression level of PD-L1 protein was not affected by ALG3 level, but the glycosylation level was significantly decreased in tumor. Similarly, the glycosylation level of PD-L1 is reduced in ALG3-KO cell in vitro. Additionally, ALG3 knockout lead to reduced tolerance of tumor cells to IFN-γ, thereby enhancing the efficacy of immunotherapy. CONCLUSION: ALG3 is a potential biomarker for poor prognosis of TNBC and may reduce the efficacy of immunotherapy by modulating the tumor microenvironment and glycosylation of PD-L1.
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Antígeno B7-H1 , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/mortalidad , Humanos , Femenino , Animales , Glicosilación , Resistencia a Antineoplásicos/genética , Pronóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Línea Celular Tumoral , Ratones , Manosiltransferasas/genética , Manosiltransferasas/metabolismo , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Proliferación Celular , Receptor de Muerte Celular Programada 1/metabolismo , Persona de Mediana Edad , Ratones Endogámicos BALB CRESUMEN
T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.