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Recent studies have highlighted the pivotal roles of T cell transcription factors TCF-1 and TOX in modulating the immune response in cancer, with TCF-1 maintaining CD8+ T cell stemness and TOX promoting T cell exhaustion. The prognostic significance of these factors in lung adenocarcinoma (LUAD) remains a critical area of investigation. The retrospective study included 191 patients with LUAD who underwent surgery, of whom 83% were in stages II and III. These patients were divided into exploratory (n = 135) and validation (n = 56) groups based on the time of diagnosis. Multiplex fluorescence immunohistochemistry was used to examine the infiltration levels of CD8+ T cells, TCF1+ CD8+ T cells, and TOX+ CD8+ T cells. The percentage of CD8+ T cells in tumor was markedly lower than that in stroma (p < 0.05). In tumor-draining lymph nodes (TDLNs) invaded by tumor, the proportion of stem-like TCF1+ CD8+ T cells was significantly decreased (p < 0.01). Importantly, higher infiltration levels of CD8+ T cells and TCF1+ CD8+ T cells were associated with improved disease-free survival (DFS) (p = 0.009 and p = 0.006, respectively) and overall survival (OS) (p = 0.018 and p = 0.010, respectively). This study underscores the potential of TCF1+ CD8+ T cells as prognostic biomarkers in LUAD, providing insights into the tumor immune microenvironment and guiding future therapeutic strategies.
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Adenocarcinoma del Pulmón , Linfocitos T CD8-positivos , Factor Nuclear 1-alfa del Hepatocito , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/mortalidad , Femenino , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Pronóstico , Masculino , Persona de Mediana Edad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Estudios Retrospectivos , Microambiente Tumoral/inmunología , Supervivencia sin Enfermedad , Proteínas del Grupo de Alta Movilidad/metabolismo , TransactivadoresRESUMEN
Not available.
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PURPOSE: This prospective study aims to evaluate the value of [18F]AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 positron emission tomography-computed tomography (PET/CT) in predicting molecular subtypes of breast cancer. METHODS: The study consecutively recruited patients suspected of having breast cancer from a single center who were prospectively enrolled from July 2023 to May 2024 and underwent [18F]AlF-NOTA-FAPI-04 PET/CT. This study compared the differences in tracer uptake among breast cancers with different adverse prognostic factors and molecular subtypes. The classification performance for each molecular subtype of breast cancer was assessed using a receiver operating characteristic (ROC) curve. RESULTS: Fifty-three participants (mean age, 51 ± 11 years; 52 females) were evaluated. Breast cancer lesions with adverse prognostic factors showed higher tracer uptake. The five different molecular subtypes exhibited varying levels of uptake. The luminal A and luminal B (HER2-negative) subtypes had relatively low uptake, while the luminal B (HER2-positive), HER2-positive, and triple-negative subtypes had relatively high uptake. ROC analysis identified the max standardized uptake value (SUVmax) as a significant classifier (AUC = 0.912, P = 0.0005) for the luminal A subtype, with 100% sensitivity and 83% specificity. For predicting the luminal B (HER2-negative) subtype, SUVmax had an AUC of 0.770 (P = 0.0015). SUVmax, with an AUC of 0.781 (P = 0.003), was used to identify the triple-negative subtype tumors, resulting in a sensitivity of 100% and specificity of 51%. Lastly, the ROC curve showed the cut-off 15.40 (AUC = 0.921, P < 0.0001) could classify luminal A & luminal B (HER2-negative), and luminal B (HER2-positive) & HER2-positive & triple-negative, yielding a sensitivity of 94% and specificity of 79%. CONCLUSION: The uptake of [18F]AlF-NOTA-FAPI-04 is significantly correlated with the molecular subtypes of breast cancer, and [18F]AlF-NOTA-FAPI-04 PET/CT is a potential tool for noninvasive identification of luminal A subtypes and guidance of FAP-targeted therapies.
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BACKGROUND: The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. METHODS: Obese mice and their lean littermates were treated with liraglutide or saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. RESULTS: Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. CONCLUSIONS: Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.
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Liraglutida , Testículo , Ratones , Animales , Masculino , Testículo/metabolismo , Liraglutida/farmacología , Liraglutida/uso terapéutico , Ratones Obesos , Análisis de Semen , Glucemia , Semen/metabolismo , Peso Corporal , Obesidad , Hormonas Esteroides Gonadales , Hormona Luteinizante , Testosterona , Hormona Folículo Estimulante , InsulinaRESUMEN
BACKGROUND: The superior efficacy of concurrent thoracic radiotherapy (TRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been proven in locally advanced and advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, the high incidence of radiation pneumonitis (RP) reduced by concurrent TRT and TKIs has attracted widespread attention. Thus, this study was designed to investigate the rate and risk factors for RP in EGFR-positive NSCLC patients simultaneously treated with aumolertinib and TRT. METHODS: We retrospectively evaluated stage IIIA-IVB NSCLC patients treated with concurrent aumolertinib and TRT between May 2020 and December 2022 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed by two senior radiologists and then graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events v5.0. All risk factors were evaluated by univariate and multivariate logistic regression analyses. RESULTS: A total of 49 patients were included, the incidence of grade ≥ 2 RP was 42.9%. Grade 2 and 3 RP were observed in 28.6% and 14.3% of patients, respectively. Grade 4 to 5 RP were not observed. the gross total volume (GTV) ≥ 21 ml and ipsilateral lung V20 ≥ 25% were risk factors for RP. The median progression-free survival (PFS) in the first-line therapy group and second-line therapy group were 23.5 months and 17.2 months, respectively (p = 0.10). CONCLUSIONS: Better local control is achieved with concurrent TRT and aumolertinib, and special attention should be given to controlling ipsilateral lung V20 and GTV to reduce the risk of RP.
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Acrilamidas , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Neumonitis por Radiación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neumonitis por Radiación/epidemiología , Neumonitis por Radiación/etiología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Estudios Retrospectivos , Dosificación Radioterapéutica , Receptores ErbB/genéticaRESUMEN
PURPOSE: The residual cancer burden index (RCB) was proposed as a response evaluation criterion in breast cancer patients treated with Neoadjuvant Chemotherapy (NAC). This study evaluated the relevance of RCB with replase-free survival (RFS). METHODS: The clinical data of 254 breast cancer patients who received NAC between 2016 and 2020 were retrospectively collected. The relationship between clinicopathologic factors and RFS was evaluated using Cox proportional hazards regression models. RFS estimates were determined by Kaplan-Meier(K-M) analysis and compared using the log-rank test. Multivariate logistic regression analysis was used to evaluate the risk factors associated with RCB. Receiver operating characteristic (ROC) curves showed the potential of the RCB and MP grading systems as biomarkers for RFS. RESULTS: At a median follow-up of 52 months, 59 patients(23.23%) developed relapse. Multivariate Cox regression showed that older age (P = 0.022), high Pathologic T stage after NAC (P = 0.023) and a high RCB score(P = 0.003) were risk factors for relapse. The outcomes of the multivariate logistic analysis indicated that RCB 0 (pathologic complete response [pCR]) was associated with HER2-positive patients (P = 0.002) and triple-negative breast cancer (TNBC) patients (P = 0.013). In addition, the RCB and MP scoring systems served as prognostic markers for patients who received NAC, and their area under curves (AUCs) were 0.691 and 0.342, respectively. CONCLUSION: These data suggest that RCB can be equally applied to predict RFS in Chinese patients with NAC. The application of RCB may help guide the selection of treatment strategies.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/patología , Pronóstico , Terapia Neoadyuvante , Neoplasia Residual/patología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Recurrencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: The antiviral drug Nirmatrelvir was found to be a key drug in controlling the progression of pneumonia during the infectious phase of COVID-19. However, there are very few options for effective treatment for cancer patients who have viral pneumonia. Glucocorticoids is one of the effective means to control pneumonia, but there are many adverse events. EGCG is a natural low toxic compound with anti-inflammatory function. Thus, this study was designed to investigate the safety and efficacy of epigallocatechin-3-gallate (EGCG) aerosol to control COVID-19 pneumonia in cancer populations. METHODS: The study was designed as a prospective, single-arm, open-label phase I/II trial at Shandong Cancer Hospital and Institute, between January 5, 2023 to March 31,2023 with viral pneumonia on radiographic signs after confirmed novel coronavirus infection. These patients were treated with EGCG nebulization 10 ml three times daily for at least seven days. EGCG concentrations were increased from 1760-8817umol/L to 4 levels with dose escalation following a standard Phase I design of 3-6 patients per level. Any grade adverse event caused by EGCG was considered a dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) is defined as the highest dose with less than one-third of patients experiencing dose limiting toxicity (DLT) due to EGCG. The primary end points were the toxicity of EGCG and CT findings, and the former was graded by Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. The secondary end point was the laboratory parameters before and after treatment. RESULT: A total of 60 patients with high risk factors for severe COVID-19 pneumonia (factors such as old age, smoking and combined complications)were included in this phase I-II study. The 54 patients in the final analysis were pathologically confirmed to have tumor burden and completed the whole course of treatment. A patient with bucking at a level of 1760 umol/L and no acute toxicity associated with EGCG has been reported at the second or third dose gradients. At dose escalation to 8817umol/L, Grade 1 adverse events of nausea and stomach discomfort occurred in two patients, which resolved spontaneously within 1 hour. After one week of treatment, CT showed that the incidence of non-progression of pneumonia was 82% (32/39), and the improvement rate of pneumonia was 56.4% (22/39). There was no significant difference in inflammation-related laboratory parameters (white blood cell count, lymphocyte count, IL-6, ferritin, C-reactive protein and lactate dehydrogenase) before and after treatment. CONCLUSION: Aerosol inhalation of EGCG is well tolerated, and preliminary investigation in cancer population suggests that EGCG may be effective in COVID-19-induced pneumonia, which can promote the improvement of patients with moderate pneumonia or prevent them from developing into severe pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05758571. Date of registration: 8 February 2023.
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COVID-19 , Catequina , Neoplasias , Neumonía Viral , Humanos , Catequina/efectos adversos , Catequina/análogos & derivados , Catequina/uso terapéutico , Oxígeno , Neumonía Viral/epidemiología , Estudios Prospectivos , Aerosoles y Gotitas Respiratorias , Resultado del TratamientoRESUMEN
Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.
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Carcinoma Hepatocelular , Proliferación Celular , Progresión de la Enfermedad , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Factor de Transcripción STAT1 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/inmunología , Quinolinas/farmacología , Quinolinas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/inmunología , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Factor de Transcripción STAT1/metabolismo , Animales , Ratones , Humanos , Proliferación Celular/efectos de los fármacos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Masculino , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunologíaRESUMEN
BACKGROUND: Bovine viral diarrhea (BVD) is an acute febrile infectious disease caused by the bovine viral diarrhea virus (BVDV), which has brought huge economic losses to the world's cattle industry. At present, commercial inactivated BVDV vaccines may cause some adverse reactions during use. This study aims to develop a safer and more efficient inactivated BVDV vaccine. METHODS: Here, we described the generation and preclinical efficacy of a hydrogen peroxide (H2O2) inactivated BVDV type 1 vaccine in mice, and administered it separately with commercial vaccine (formaldehyde inactivated) in mice to study its efficacy. RESULTS: The BVDV type 1 IgG, IFN- γ, IL-4 and neutralizing antibody in the serum of the H2O2 inactivated vaccine group can be maintained in mice for 70 days. The IgG level reached its maximum value of 0.67 on the 42nd day, significantly higher than the commercial formaldehyde inactivated BVDV type 1 vaccine. IFN- γ and IL-4 reached their maximum values on the 28th day after immunization, at 123.16 pg/ml and 143.80 pg/ml, respectively, slightly higher than commercial vaccines, but the effect was not significant. At the same time the BVDV-1 neutralizing antibody titer reached a maximum of 12 Nu on the 42nd day post vaccination. CONCLUSIONS: The H2O2 inactivated BVDV vaccine has good safety and immunogenicity, which provides a potential solution for the further development of an efficient and safe BVDV vaccine.
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Diarrea Mucosa Bovina Viral , Enfermedades de los Bovinos , Virus de la Diarrea Viral Bovina Tipo 1 , Virus de la Diarrea Viral Bovina , Vacunas Virales , Animales , Bovinos , Ratones , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Diarrea/veterinaria , Formaldehído , Peróxido de Hidrógeno , Inmunoglobulina G , Interleucina-4 , Vacunas de Productos InactivadosRESUMEN
PURPOSE: To develop a radiotherapy positioning system based on Point Cloud Registration (PCR) and Augmented Reality (AR), and to verify its feasibility. METHODS: The optimal steps of PCR were investigated, and virtual positioning experiments were designed to evaluate its accuracy and speed. AR was implemented by Unity 3D and Vuforia for initial position correction, and PCR for precision registration, to achieve the proposed radiotherapy positioning system. Feasibility of the proposed system was evaluated through phantom positioning tests as well as real human positioning tests. Real human tests involved breath-holding positioning and free-breathing positioning tests. Evaluation metrics included 6 Degree of Freedom (DOF) deviations and Distance (D) errors. Additionally, the interaction between CBCT and the proposed system was envisaged through CBCT and optical cross-source PCR. RESULTS: Point-to-plane iterative Closest Point (ICP), statistical filtering, uniform down-sampling, and optimal sampling ratio were determined for PCR procedure. In virtual positioning tests, a single registration took only 0.111 s, and the average D error for 15 patients was 0.015 ± 0.029 mm., Errors of phantom tests were at the sub-millimeter level, with an average D error of 0.6 ± 0.2 mm. In the real human positioning tests, the average accuracy of breath-holding positioning was still at the sub-millimeter level, where the errors of X, Y and Z axes were 0.59 ± 0.12 mm, 0.54 ± 0.12 mm, and 0.52 ± 0.09 mm, and the average D error was 0.96 ± 0.22 mm. In the free-breathing positioning, the average errors in X, Y, and Z axes were still less than 1 mm. Although the mean D error was 1.93 ± 0.36 mm, it still falls within a clinically acceptable error margin. CONCLUSION: The AR and PCR-guided radiotherapy positioning system enables markerless, radiation-free and high-accuracy positioning, which is feasible in real-world scenarios.
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Realidad Aumentada , Humanos , Imagenología Tridimensional/métodos , Estudios de Factibilidad , Fantasmas de ImagenAsunto(s)
Inmunoterapia , Neoplasias Pulmonares , Radiocirugia , Humanos , Radiocirugia/métodos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Inmunoterapia/métodos , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estadificación de Neoplasias , Terapia CombinadaRESUMEN
Copper is an essential trace element obtained from food. There is a paucity of observational or prospective studies that have investigated the relationship between copper and melanoma risk. Copper serves as a cofactor for pivotal enzymes involved in mitochondrial respiration, antioxidant defense, and neurotransmitter synthesis. Undoubtedly, copper plays an indispensable role in the initiation and progression of tumors, particularly melanoma; however, further investigations are warranted to elucidate the underlying mechanisms linking copper and melanoma risk. Given the availability of dietary copper and serum copper data in the NHANES database, we conducted an investigation into the association between dietary copper intake and serum copper levels with melanoma risk. We enrolled 26,401 individuals with dietary copper data in the 2007-2018 NHANES database. To mitigate confounding variables, a propensity score matching (PSM) was performed. To assess the association between dietary copper intake and melanoma risk, we employed a multivariate logistic regression analysis before and after PSM. The restricted cubic spline analysis was utilized to determine whether there is a non-linear relationship between dietary copper intake and melanoma risk, with subgroup analysis conducted to determine beneficiaries. Then, those with blood copper data from the enrolled population with dietary copper intake were screened out, and subsequently, multivariate logistic regression models were subsequently constructed to investigate the association between serum copper levels and melanoma risk after PSM. Mendelian analysis was further utilized to validate the results of the NHANES database using serum copper as the exposure factor and melanoma as the outcome variable. The study found that melanoma risk was associated with dietary copper intake before and after PSM, demonstrated by multiple logistic regression. The relationship between dietary copper intake and melanoma risk was non-linear, with a reduced risk observed above approximately 2.5 mg/day, as shown by the RCS. The evidence suggests that an increased intake of copper is linked to a decreased risk of melanoma. To clarify the mechanism behind the increased risk of melanoma due to higher dietary copper intake, we analyzed the population data from the NHANES database on serum copper and dietary copper intake. Our results indicated that there is no causal relationship between serum copper and melanoma risk. Mendelian randomization analysis of multi-database data sources confirmed the conclusion of the NHANES database analysis. Dietary copper is a protective factor against melanoma, and serum copper or blood copper is not associated with melanoma risk. This suggests that serum or blood copper is not responsible for the protective effect of dietary copper intake on melanoma risk, and the mechanisms need to be further investigated.
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Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.
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Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Neoplasias/patología , Metabolismo Energético , Microambiente TumoralRESUMEN
Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC. Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy (iRT) have generated encouraging results. This review discusses the existing studies and prospective directions of chemotherapy-free iRT strategies in unresectable LA-NSCLC. Although the initial findings of chemotherapy-free iRT strategies have shown promising efficacy, we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free iRT. These challenges include determining the optimal dose and fractionation, precise target volume delineation, and identification of additional suitable patient cohorts. Furthermore, the feasibility of chemotherapy-free iRT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Prospectivos , Quimioradioterapia/métodosRESUMEN
Immunotherapy has revolutionized cancer treatment. However, it's well-recognized that a considerable proportion of patients fail to benefit from immunotherapy, and to improve immunotherapy response is clinically urgent. Insufficient immune infiltration and immunosuppressive tumor microenvironments (TME) are main contributors to immunotherapy resistance. Thus sustaining functional self-renewal capacity for immune cells and subverting immune-suppressive signals are potential strategies for boosting the efficacy of immunotherapy. Interleukin-21 (IL-21), a crucial cytokine, which could enhance cytotoxic function of immune cells and reduces immunosuppressive cells enrichment in TME, shows promising orientations as an immunoadjuvant in tumor immunotherapy. This review focuses on IL-21 in cancer treatment, including function and mechanisms of IL-21, preclinical and clinical studies, and future directions for IL-21-assisted therapies.
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Antineoplásicos , Neoplasias , Humanos , Inmunoterapia , Interleucinas/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias/patologíaRESUMEN
Background: Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2+ TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker. Methods: We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2+ TAM subpopulations (CD68+SHP2+, CD68+CD86+, CD68 + 206+, CD68+ CD86+SHP2+, CD68+ CD206+SHP2+) and T cells (CD8+ Granzyme B +) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests. Results: In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68+ SHP2+ TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68+SHP2+ TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68+SHP2+ subset proportion was positively correlated with the CD68+CD206+ subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001). Conclusions: The high infiltration of CD68+SHP2+ TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.
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Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Microambiente Tumoral , Macrófagos Asociados a Tumores , Humanos , Microambiente Tumoral/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Antígenos CD/metabolismo , Masculino , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Persona de Mediana Edad , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Pronóstico , Adulto , Molécula CD68RESUMEN
Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.
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Isocitrate dehydrogenase 1 mutant (IDH1mut) tumors respond poorly to immunotherapy, but are more sensitive to chemoradiotherapy and poly (ADP-ribose) polymerase inhibition (PARPi). Accordingly, some efforts have aimed to capitalize on the IDH1 mutation rather than reverse it. Moreover, radiotherapy (RT) and PARPi can stimulate antitumor immunity, raising the possibility of reversing the immunosuppression caused by IDH1 mutation while killing the tumor. To assess this possibility, we treated IDH1mut tumors and cells with RT + PARPi. RT + PARPi showed enhanced efficacy over either modality alone both in vitro and in vivo. RT + PARPi induced more DNA damage and activated the cGAS-STING pathway more. IFNß, CXCL10, and CCL5 were also more highly expressed at both the mRNA and protein levels. In two different tumor models, RT + PARPi increased infiltration and cytolytic function of CD8+ T cells, with one model also showing increased CD8+T cell proliferation. RT+PARPi also increased PD-L1 expression and enhanced checkpoint inhibition. Knocking out cGAS reversed the increased CD8+ T cell infiltration and the antitumor effect of RT+PARPi. We conclude that RT + PARPi reshapes the IDH1mut tumor immunosuppressive microenvironment, thereby augmenting checkpoint inhibition.
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Neoplasias , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/radioterapia , Mutación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Terapia de Inmunosupresión , Nucleotidiltransferasas , Microambiente Tumoral , Isocitrato Deshidrogenasa/genéticaRESUMEN
Introduction: The variability and unpredictability of immune checkpoint inhibitors (ICIs) in treating brain metastases (BMs) in patients with advanced non-small cell lung cancer (NSCLC) is the main concern. We assessed the utility of novel imaging biomarkers (radiomics) for discerning patients with NSCLC and BMs who would derive advantages from ICIs treatment. Methods: Data clinical outcomes and pretreatment magnetic resonance images (MRI) were collected on patients with NSCLC with BMs treated with ICIs between June 2019 and June 2022 and divided into training and test sets. Metastatic brain lesions were contoured using ITK-SNAP software, and 3748 radiomic features capturing both intra- and peritumoral texture patterns were extracted. A clinical radiomic nomogram (CRN) was built to evaluate intracranial progression-free survival, progression-free survival, and overall survival. The prognostic value of the CRN was assessed by Kaplan-Meier survival analysis and log-rank tests. Results: In the study, a total of 174 patients were included, and 122 and 52 were allocated to the training and validation sets correspondingly. The intratumoral radiomic signature, peritumoral radiomic signature, clinical signature, and CRN predicted intracranial objective response rate. Kaplan-Meier analyses showed a significantly longer intracranial progression-free survival in the low-CRN group than in the high-CRN group (p < 0.001). The CRN was also significantly associated with progression-free survival (p < 0.001) but not overall survival. Discussion: Radiomics biomarkers from pretreatment MRI images were predictive of intracranial response. Pretreatment radiomics may allow the early prediction of benefits.
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Imagen por Resonancia Magnética , Nomogramas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Imagen por Resonancia Magnética/métodos , Masculino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidad , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pronóstico , Resultado del Tratamiento , AdultoRESUMEN
BACKGROUND: The treatment of lung cancer has witnessed significant progress, leading to improved survival rates among patients. It is important to assess the individual contributions of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) to overall lung-cancer incidence and mortality trends based population, especially sex difference. METHODS: We analyzed lung cancer mortality based on subtype, gender, and calendar year. The Joinpoint software was used to identify any changes in incidence and trends in mortality. RESULTS: Incidence and incidence-based mortality declined from 2001 to 2019 both NSCLC and SCLC annually. The most significant decrease occurred between 2016 and 2019 with annual percent change of 5.71%. From 2012 to 2016, the incidence-based mortality of SCLC in women changed by 2.7% in tandem with incidence decreased 2.84%. Remarkably, the incidence-based mortality for women declined notably by 5.23% between 2016 and 2019, even as the incidence showed a less extent of decreasing (-2.59%). The survival rate for women was 15.2% in 2001, 19.3% in 2016, it had increased to 21.3% in 2018 but similar trends not in men. The survival curve showed the change in survival outcomes over time among men and women (median overall survival: 13 vs 23months) receiving immunotherapy for SCLC. CONCLUSION: Population-level mortality from NSCLC and SCLC in the United States fell sharply from 2016 to 2019 as incidence deceased, and survival improved substantially. Our analysis suggests that approval for and use of immunotherapy may explain the mortality reduction observed during this period, with significant benefits especially for SCLC patient in women.