RESUMO
PURPOSE: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. EXPERIMENTAL DESIGN: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. RESULTS: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. CONCLUSIONS: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Etoposídeo , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Microambiente Tumoral , Humanos , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Etoposídeo/uso terapêutico , Etoposídeo/farmacologia , Etoposídeo/administração & dosagem , Idoso , Pessoa de Meia-Idade , Perfilação da Expressão Gênica/métodos , Adulto , Estadiamento de NeoplasiasRESUMO
OBJECTIVES: To identify potential diagnostic markers for small cell lung cancer (SCLC) and investigate the correlation with immune cell infiltration. METHODS: GSE149507 and GSE6044 were used as the training group, while GSE108055 served as validation group A and GSE73160 served as validation group B. Differentially expressed genes (DEGs) were identified and analyzed for functional enrichment. Machine learning (ML) was used to identify candidate diagnostic genes for SCLC. The area under the receiver operating characteristic curves was applied to assess diagnostic efficacy. Immune cell infiltration analyses were carried out. RESULTS: There were 181 DEGs identified. The gene ontology analysis showed that DEGs were enriched in 455 functional annotations, some of which were associated with immunity. The kyoto encyclopedia of genes and genomes analysis revealed that there were 9 signaling pathways enriched. The disease ontology analysis indicated that DEGs were related to 116 diseases. The gene set enrichment analysis results displayed multiple items closely related to immunity. ZWINT and NRCAM were screened using ML and further validated as diagnostic genes. Significant differences were observed in SCLC with normal lung tissue samples among immune cell infiltration characteristics. Strong associations were found between the diagnostic genes and immune cell infiltration. CONCLUSION: This study identified 2 diagnostic genes, ZWINT and NRCAM, that were related to immune cell infiltration by integrating bioinformatics analysis and ML algorithms. These genes could serve as potential diagnostic biomarkers and provide possible molecular targets for immunotherapy in SCLC.
Assuntos
Biologia Computacional , Neoplasias Pulmonares , Aprendizado de Máquina , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Biomarcadores Tumorais/genética , Algoritmos , Perfilação da Expressão Gênica , Ontologia GenéticaRESUMO
Immune cells play a vital role in the development and progression of lung cancer (LC). We aimed to explore the causal role of immune cells in LC with Mendelian randomization (MR) study. Summary statistic data used in the study were obtained from genome-wide association studies (GWAS). A comprehensive two-sample MR was carried out to explore the causal role of 731 immune cell traits (ICTs) in LC, Non-small cell lung cancer (NSCLC), and Small cell lung cancer (SCLC). An inverse-variance weighted (IVW) approach was applied to present the MR estimates. The heterogeneity test was performed using Cochran's Q statistic. MR-Egger intercept test and MR-PRESSO were utilized for the pleiotropy test. MR showed that 15, 31, and 11 ICTs had protective effects on LC, NSCLC, and SCLC, respectively, and 12, 31, and 11 ICTs had adverse effects on LC, NSCLC, and SCLC, respectively. Of note, CD3 on CD28+ CD4+ in the Treg panel could significantly increase the risk of LC, as well as NSCLC and SCLC. Moreover, the MR results revealed that LC was vital in IgD on IgD+ in the B cell panel and NSCLC on CCR2 on CD14- CD16- in the Monocyte panel. Our study revealed multiple close connections between immune cells and LC.
Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Análise da Randomização Mendeliana , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Patients receiving PD-(L)1 inhibitors frequently encounter unusual side effects known as immune-related adverse events (irAEs). However, the correlation of irAEs development with clinical response in small cell lung cancer (SCLC) is unknown. METHOD: This retrospective study enrolled 244 stage IV SCLC patients who receiving PD-(L)1 inhibitors from 3 cancer centers. The correlation of irAEs with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: 140 in 244 (57%) patients experienced irAEs, with 122 (87.1%) experiencing one and 18 (12.9%) experiencing two or more. Compared to patient without irAEs, those developing irAEs had higher ORR (73.6% vs. 52.9%, P < 0.001) and DCR (97.9% vs. 79.8%, P < 0.001), as well as prolonged median PFS (8.8 vs. 4.5 months, P < 0.001) and OS (23.2 vs. 21.6 months, P < 0.05). Among the different spectra of irAEs, thyroid dysfunction, rash, and pneumonitis were the most powerful indicator for improved PFS. When analyzed as a time-dependent covariate, the occurrence of irAEs was associated with significant improvement in PFS rather than in OS. Furthermore, patients experiencing multisystem irAEs displayed a longer PFS and OS compared with single-system irAEs and the irAE-free ones. IrAEs grade and steroid use did not impact the predictive value of irAEs on PFS. CONCLUSION: The presence of irAEs predicts superior clinical benefit in SCLC. Patients who develop multi-system irAEs may have an improved survival than those developed single-system irAEs and no-irAEs. This association persists even when systemic corticosteroids were used for irAEs management.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Estudos Retrospectivos , Masculino , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , Resultado do Tratamento , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Intervalo Livre de ProgressãoRESUMO
Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of small cell lung cancer (SCLC), but only a minority of patients benefit from this therapy. Therefore, it is critical to identify potential risk factors that could predict the efficacy of ICI treatment in SCLC patients and identify patient subgroups who may benefit the most from ICI therapy. Methods: Our study included a total of 183 SCLC patients who had received at least one dose of ICI treatment. We utilized both logistic regression and Cox proportional hazard regression to evaluate whether various patient clinical factors and serum biomarkers could serve as predictors of patient response to treatment and overall survival (OS) during ICI therapy. Results: Logistic regression showed that patients with a history of surgery (p=0.003, OR 9.06, 95% CI: (2.17, 37.9)) and no metastasis (p=0.008, OR 7.82, 95% CI: (1.73, 35.4)) exhibited a higher odds of response to ICI treatment. Cox regression analyses demonstrated that pretreatment blood albumin (p=0.003, HR 1.72, 95% CI: (1.21, 2.45)) and derived neutrophil to lymphocyte ratio (dNLR) (p=0.003, HR 1.71, 95% CI: (1.20-2.44)) were independent predictors for OS in SCLC patients. By establishing a pre-treatment prognostic scoring system based on baseline albumin and dNLR, we found that patients with high albumin and low dNLR exhibited a significantly better prognosis than those with low albumin and high dNLR in both the full (P<.0001, HR 0.33, 95% CI: 0.20-0.55) and the metastatic cohort (P<.0001, HR 0.28, 95% CI: 0.15-0.51). The better prognostic group also had younger age, higher BMI and lower systemic inflammatory biomarker values than the unfavorable group (P<.0001). Conclusion: Our data reveals the significant role of metastasis status and treatment history in predicting the initial response of SCLC patients to ICI treatment. However, baseline serum albumin and dNLR provide a more precise prognostic prediction for patient OS. The scoring system based on albumin and dNLR enhances the ability to stratify patient prognosis and holds the potential to guide clinical decision-making for SCLC patients undergoing ICI therapy.
Assuntos
Biomarcadores Tumorais , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Linfócitos , Neutrófilos , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Neutrófilos/imunologia , Masculino , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/imunologia , Idoso , Pessoa de Meia-Idade , Linfócitos/imunologia , Biomarcadores Tumorais/sangue , Prognóstico , Albumina Sérica Humana/análise , Albumina Sérica/análise , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Contagem de LinfócitosRESUMO
PURPOSE: To clarify the prognostic role of the Gustave Roussy immune (GRIm) score in lung cancer. METHODS: The PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases were searched up to March 30, 2024. The primary outcomes included overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the associations between the GRIm score and survival, and subgroup analyses were performed based on pathological type (non-small cell lung cancer vs. small cell lung cancer), tumor stage (advanced vs. limited stage) and treatment approach (immune checkpoint inhibitor vs. surgery vs. chemotherapy). RESULTS: Eight studies with 1,333 participants were included. The pooled results showed that a higher GRIm score predicted worse OS (HR = 1.96, 95% CI: 1.54-2.49, P < 0.001) and PFS (HR = 1.64, 95% CI: 1.22-2.21, P = 0.001). Subgroup analyses for OS and PFS showed similar results. However, subgroup analyses for PFS indicated that the association between the GRIm score and PFS was nonsignificant among patients with small cell lung cancer (P = 0.114) and among patients treated with chemotherapy (P = 0.276). CONCLUSION: The GRIm score might serve as a novel prognostic factor for lung cancer. Additional studies are still needed to verify these findings.
Assuntos
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Prognóstico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estadiamento de NeoplasiasRESUMO
UICC stage IV small-cell lung cancer (SCLC) is a highly aggressive malignancy without curative treatment options. Several randomized trials have demonstrated improved survival rates through the addition of checkpoint inhibitors to first-line platin-based chemotherapy. Consequently, a combination of chemo- and immunotherapy has become standard palliative treatment. However, no reliable predictive biomarkers for treatment response exist. Neither PD-L1 expression nor tumor mutational burden have proven to be effective predictive biomarkers. In this study, we compared the cellular immune statuses of SCLC patients to a healthy control cohort and investigated changes in peripheral blood B, T, and NK lymphocytes, as well as several of their respective subsets, during treatment with immunochemotherapy (ICT) using flow cytometry. Our findings revealed a significant decrease in B cells, while T cells showed a trend to increase throughout ICT. Notably, high levels of exhausted CD4+ and CD8+ cells, alongside NK subsets, increased significantly during treatment. Furthermore, we correlated decreases/increases in subsets after two cycles of ICT with survival. Specifically, a decrease in Th17 cells indicated a better overall survival. Based on these findings, we suggest conducting further investigation into Th17 cells as a potential early predictive biomarkers for response in patients receiving palliative ICT for stage IV SCLC.
Assuntos
Biomarcadores Tumorais , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Células Th17 , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Células Th17/imunologia , Células Th17/metabolismo , Estadiamento de Neoplasias , Imunoterapia/métodos , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/efeitos dos fármacos , Adulto , PrognósticoRESUMO
Background: The efficacy and safety of different immunosuppressants combined with chemotherapy in treating patients with small-cell lung cancer (extensive-disease small-cell lung cancer, limited-disease small-cell lung cancer and relapsed small-cell lung cancer) are still unknown, and there are no reports directly comparing the efficacy and safety of other immunotherapies. Objective: This study aimed to compare the efficacy and safety of first-line immunotherapy combined with chemotherapy in patients with small-cell lung cancer. Method: We searched Pubmed, Embase, Cochrane Library, CNKI, and Wanfang databases for relevant articles published from inception to November 11, 2020. The risk of bias of the included studies was conducted using the Cochrane risk-of-bias (RoB) tool. Multiple Bayesian network meta-analyses were performed. They conducted data analysis using R Studio and STATA version 15.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), stability of response (SOR), duration of response (DOR) and adverse events of grade 3 or higher (AE grade≥3). A 95% confidence interval (CI) was provided for each estimate. Results: This meta-analysis included 16 RCT studies with 5898 patients. For OS, relative to chemotherapy (MD=-4.49; 95%CI [-7.97, -1.03]), durvalumab plus tremelimumab (MD=-4.62; 95%CI [-9.08, -0.11]), ipilimumab (MD=-4.26; 95%CI [-8.01, -0.3]) and nivolumab(MD=-5.66; 95%CI [-10.44, -1.11]) and nivolumab plus ipilimumab (MD=-4.56; 95%CI [-8.7, -0.1]), serplulimab can significantly increase the OS of SCLC patients. There was no significant difference between PFS, SOR and DOR. Analysis of AE showed that different immunotherapy combined chemotherapy regimens were similar to single chemotherapy regarding the overall incidence of AE grade≥3. However, after the cumulative ranking of the common symptoms of different adverse reactions, it was found that nivolumab ranked first in the occurrence probability of anemia (99.08%), fatigue (84.78%), and decreased appetite (89.66%). durvalumab was the most likely in nausea (75.4%). Pembrolizumab (76.24%) was most likely to cause pruritus. Chemotherapy combined with immunotherapy caused less diarrhea than chemotherapy alone (80.16%). Conclusions: According to our analysis, serplulimab combined with chemotherapy is more likely to show better efficacy with a manageable safety profile for small-cell lung cancer. However, the evidence for this comparison shows some limitations due to the number of literature. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023486053.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Imunoterapia , Neoplasias Pulmonares , Metanálise em Rede , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imunoterapia/métodos , Resultado do Tratamento , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
This report describes the case of a 48-year-old woman who presented with sternoclavicular joint arthritis after administration of an immune checkpoint inhibitor (ICI), durvalumab, for small cell lung carcinoma. The onset of arthritis transpired 18 months after the commencement of the ICI therapeutic regimen and demonstrated resilience to glucocorticoid treatment. After excluding infectious aetiologies and metastatic involvement, the patient was diagnosed with ICI-induced arthritis (ICI-IA). Considering the articular implications akin to the SAPHO syndrome, the patient was treated with infliximab, resulting in complete resolution. This finding implies that biological DMARDs can serve as effective interventions for ICI-induced sternoclavicular joint arthritis. Given the heterogeneous nature of its pathogenesis, the selection of therapeutic agents may require customization based on the distinct clinical presentation of each individual case.
Assuntos
Artrite , Inibidores de Checkpoint Imunológico , Infliximab , Articulação Esternoclavicular , Humanos , Feminino , Infliximab/uso terapêutico , Infliximab/efeitos adversos , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Artrite/tratamento farmacológico , Artrite/induzido quimicamente , Artrite/etiologia , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Resultado do Tratamento , Anticorpos MonoclonaisRESUMO
INTRODUCTION: Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. METHODS: In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. RESULTS: Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. CONCLUSION: Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.
Assuntos
Autoanticorpos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Feminino , Autoanticorpos/sangue , Autoanticorpos/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/sangue , Idoso , Pessoa de Meia-Idade , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/imunologia , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Adulto , Prognóstico , Neurônios/patologia , Neurônios/imunologiaRESUMO
BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Feminino , Masculino , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais/uso terapêutico , Resultado do Tratamento , Estadiamento de Neoplasias , Anticorpos Monoclonais Humanizados/uso terapêutico , Prognóstico , AdultoRESUMO
BACKGROUND AND PURPOSE: Recently, the emergence of immune checkpoint inhibitors has significantly improved the survival of patients with extensive-stage small cell lung cancer. However, not all patients can benefit from immunotherapy; therefore, there is an urgent need for precise predictive markers to screen the population for the benefit of immunotherapy. However, single markers have limited predictive accuracy, so a comprehensive predictive model is needed to better enable precision immunotherapy. The aim of this study was to establish a prognostic model for immunotherapy in ES-SCLC patients using basic clinical characteristics and peripheral hematological indices of the patients, which would provide a strategy for the clinical realization of precision immunotherapy and improve the prognosis of small cell lung cancer patients. METHODS: This research retrospectively collected data from ES-SCLC patients treated with PD-1/PD-L1 inhibitors between March 1, 2019, and October 31, 2022, at Harbin Medical University Cancer Hospital. The study data was randomly split into training and validation sets in a 7:3 ratio. Variables associated with patients' overall survival were screened and modeled by univariate and multivariate Cox regression analyses. Models were presented visually via Nomogram plots. Model discrimination was evaluated by Harrell's C index, tROC, and tAUC. The calibration of the model was assessed by calibration curves. In addition, the clinical utility of the model was assessed using a DCA curve. After calculating the total risk score of patients in the training set, patients were stratified by risk using percentile partitioning. The Kaplan-Meier method was used to plot OS and PFS survival curves for different risk groups and response statuses at different milestone time points. Differences in survival time groups were compared using the chi-square test. Statistical analysis software included R 4.1.2 and SPSS 26. RESULTS: This study included a total of 113 ES-SCLC patients who received immunotherapy, including 79 in the training set and 34 in the validation set. Six variables associated with poorer OS in patients were screened by Cox regression analysis: liver metastasis (P = 0.001), bone metastasis (P = 0.013), NLR < 2.14 (P = 0.005), LIPI assessed as poor (P < 0.001), PNI < 51.03 (P = 0.002), and LDH ≥ 146.5 (P = 0.037). A prognostic model for immunotherapy in ES-SCLC patients was constructed based on the above variables. The Harrell's C-index in the training and validation sets of the model was 0.85 (95% CI 0.76-0.93) and 0.88 (95% CI 0.76-0.99), respectively; the AUC values corresponding to 12, 18, and 24 months in the tROC curves of the training set were 0.745, 0.848, and 0.819 in the training set and 0.858, 0.904 and 0.828 in the validation set; the tAUC curves show that the overall tAUC is > 0.7 and does not fluctuate much over time in both the training and validation sets. The calibration plot demonstrated the good calibration of the model, and the DCA curve indicated that the model had practical clinical applications. Patients in the training set were categorized into low, intermediate, and high risk groups based on their predicted risk scores in the Nomogram graphs. In the training set, 52 patients (66%) died with a median OS of 15.0 months and a median PFS of 7.8 months. Compared with the high-risk group (median OS: 12.3 months), the median OS was significantly longer in the intermediate-risk group (median OS: 24.5 months, HR = 0.47, P = 0.038) and the low-risk group (median OS not reached, HR = 0.14, P = 0.007). And, the median PFS was also significantly prolonged in the intermediate-risk group (median PFS: 12.7 months, HR = 0.45, P = 0.026) and low-risk group (median PFS not reached, HR = 0.12, P = 0.004) compared with the high-risk group (median PFS: 6.2 months). Similar results were obtained in the validation set. In addition, we observed that in real-world ES-SCLC patients, at 6 weeks after immunotherapy, the median OS was significantly longer in responders than in non-responders (median OS: 19.5 months vs. 11.9 months, P = 0.033). Similar results were obtained at 12 weeks (median OS: 20.7 months vs 11.9 months, P = 0.044) and 20 weeks (median OS: 20.7 months vs 11.7 months, P = 0.015). Finally, we found that in the real world, ES-SCLC patients without liver metastasis (P = 0.002), bone metastasis (P = 0.001) and a total number of metastatic organs < 2 (P = 0.002) are more likely to become long-term survivors after receiving immunotherapy. CONCLUSION: This study constructed a new prognostic model based on basic patient clinical characteristics and peripheral blood indices, which can be a good predictor of the prognosis of immunotherapy in ES-SCLC patients; in the real world, the response status at milestone time points (6, 12, and 20 weeks) can be a good indicator of long-term survival in ES-SCLC patients receiving immunotherapy.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Masculino , Feminino , Estudos Retrospectivos , Prognóstico , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/imunologia , China/epidemiologia , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Nomogramas , Adulto , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
Small-cell lung cancer (SCLC) cases represent approximately 15% of all lung cancer cases, remaining a recalcitrant malignancy with poor survival and few treatment options. In the last few years, the addition of immunotherapy to chemotherapy improved clinical outcomes compared to chemotherapy alone, resulting in the current standard of care for SCLC. However, the advantage of immunotherapy only applies to a few SCLC patients, and predictive biomarkers selection are lacking for SCLC. In particular, due to some features of SCLC, such as high heterogeneity, elevated cell plasticity, and low-quality tissue samples, SCLC biopsies cannot be used as biomarkers. Therefore, the characterization of the tumor and, subsequently, the selection of an appropriate therapeutic combination may benefit greatly from liquid biopsy. Soluble factors, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) are now useful tools in the characterization of SCLC. This review summarizes the most recent data on biomarkers detectable with liquid biopsy, emphasizing their role in supporting tumor detection and their potential role in SCLC treatment choice.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Carcinoma de Pequenas Células do Pulmão , Humanos , Biópsia Líquida/métodos , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/diagnóstico , Imunoterapia/métodos , Biomarcadores Tumorais/metabolismo , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , DNA Tumoral Circulante/sangue , Vesículas Extracelulares/metabolismoRESUMO
Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.
Assuntos
Complexo CD3 , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares , Proteínas de Membrana , Carcinoma de Pequenas Células do Pulmão , Linfócitos T , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Complexo CD3/imunologia , Animais , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Linhagem Celular Tumoral , Ativação Linfocitária/imunologia , Feminino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Platinum-based chemotherapy plus PD1 axis blockade is the standard of care in the first-line treatment of extensive-stage small cell lung cancer (SCLC). Despite the robust and consistent increase in long-term survival with PD1 axis inhibition, the magnitude of the benefit from immunotherapy seems lower than that for other solid tumors. Several immune evasive mechanisms have been shown to be prominently altered in human SCLC, including T-cell exclusion, downregulation of components of the MHC class I antigen processing and presentation machinery, or upregulation of macrophage inhibitory checkpoints, among others. New immunotherapies aiming to target some of these dominant immune suppressive features are being intensively evaluated preclinically and clinically in SCLC. They include strategies to enhance the efficacy and/or reverse features that promote intrinsic resistance to PD1 axis inhibition (e.g., restoring MHC class I deficiency and targeting DNA damage response) and novel immunomodulatory agents beyond T-cell checkpoint blockers (e.g., T cell-redirecting strategies, antibody-drug conjugates, or macrophage checkpoint blockers). Among them, delta-like ligand 3-targeted bispecific T-cell engagers have shown the most compelling preliminary evidence of clinical efficacy and hold promise as therapies that might contribute to further improve patient outcomes in this disease. In this study, we first provide a brief overview of key tumor microenvironment features of human SCLC. Then, we update the current clinical evidence with immune checkpoint blockade and review other emerging immunotherapy strategies that are gaining increasing attention in SCLC. We finally summarize our future perspective on immunotherapy and precision oncology for this disease.
Assuntos
Imunoterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Microambiente Tumoral/imunologia , AnimaisRESUMO
The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.
Assuntos
Evolução Molecular , Imunoterapia , Neoplasias Pulmonares , Platina , Carcinoma de Pequenas Células do Pulmão , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células Clonais/efeitos dos fármacos , Células Clonais/metabolismo , Células Clonais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Genes myc/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Platina/farmacologia , Platina/uso terapêutico , Recidiva , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
Small cell lung cancer (SCLC), recognized as the most aggressive subtype of lung cancer, presents an extremely poor prognosis. Currently, patients with small cell lung cancer face a significant dearth of effective alternative treatment options once they experience recurrence and progression after first-line therapy. Despite the promising efficacy of immunotherapy, particularly immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and various other tumours, its impact on significantly enhancing the prognosis of SCLC patients remains elusive. DLL3 has emerged as a compelling target for targeted therapy in SCLC due to its high expression on the membranes of SCLC and other neuroendocrine carcinoma cells, with minimal to no expression in normal cells. Our previous work led to the development of a novel multiple chain chimeric antigen receptor (CAR) leveraging the TREM1 receptor and DAP12, which efficiently activated T cells and conferred potent cell cytotoxicity. In this study, we have developed a DLL3-TREM1/DAP12 CAR-T (DLL3-DT CAR-T) therapy, demonstrating comparable anti-tumour efficacy against SCLC cells in vitro. In murine xenograft and patient-derived xenograft models, DLL3-DT CAR-T cells exhibited a more robust tumour eradication efficiency than second-generation DLL3-BBZ CAR-T cells. Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Imunoterapia Adotiva , Neoplasias Pulmonares , Proteínas de Membrana , Receptores de Antígenos Quiméricos , Carcinoma de Pequenas Células do Pulmão , Receptor Gatilho 1 Expresso em Células Mieloides , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Humanos , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Linhagem Celular Tumoral , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos SCID , FemininoRESUMO
Background: Despite numerous immunotherapy and chemotherapy regimens available for patients with extensive-stage small cell lung cancer (ES-SCLC), it remains unclear which regimen is the most effective and safest; relative studies comparing such regimens are scarce. Objective: The aim of this study was to investigate the efficacy and safety of first-line immunotherapy combinations with chemotherapy for patients with extensive-stage small cell lung cancer. In addition, for the first time, comparisons among the first-line systemic regimens on OS and PFS in ES-SCLC by each time node were made. Methods: Databases including PubMed, Embase, Cochrane Library, Scopus, Google Scholars, and ClinicalTrials.gov, and major international conferences were searched for randomized controlled trials (RCTs) regarding comparing immunotherapy combinations with chemotherapy as first-line treatments for patients with advanced ES-SCLC from inception to 1 November. Hazard ratios (HRs) and odds ratios (ORs) were generated for dichotomous variants by RStudio 4.2.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (Grade ≥ 3 AEs). Results: Eventually, a total of nine RCTs reporting 4,352 individuals with nine regimens were enrolled. The regimens were ipilimumabnu (Ipi), atezolizumab (Atez), durvalumab plus tremelimumab (Durv-Trem), durvalumab (Durv), pembrolizumab (Pemb), adebrelimab (Adeb), serplulimab (Serp), atezolizumab plus tiragolumab (Atez-Tira), and nivolumab (Nivo). With regard to OS, serplulimab (HR = 0.63, 95% CI: 0.49 to 0.81) was found to yield the best OS benefit when compared with chemotherapy. Meanwhile, serplulimab had the highest probability (46.11%) for better OS. Furthermore, compared with chemotherapy, serplulimab significantly increased the OS rate from the 6th to the 21st month. With regard to PFS, serplulimab (HR = 0.47, 95% CI: 0.38 to 0.59) was found to yield the best PFS benefit when compared with chemotherapy. Simultaneously, serplulimab had the highest probability (94.48%) for better PFS. Serplulimab was also a long-lasting first-line regimen in both OS and PFS from a longitudinal perspective. In addition, there was no significant difference among the various treatment options for ORR and grade ≥3 AEs. Conclusion: Considering OS, PFS, ORR, and safety profiles, serplulimab with chemotherapy should be recommended as the best therapy for patients with ES-SCLC. Certainly, more head-to-head studies are needed to confirm these findings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022373291.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Metanálise em Rede , Nivolumabe , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-ß) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8+ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Proteínas de Membrana , Proteínas Tirosina Quinases , Fator de Transcrição STAT1 , Carcinoma de Pequenas Células do Pulmão , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT1/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
Bioinformatics methods are used to construct an immune gene prognosis assessment model for patients with non-small cell lung cancer (NSCLC), and to screen biomarkers that affect the occurrence and prognosis of NSCLC. The transcriptomic data and clinicopathological data of NSCLC and cancer-adjacent normal tissues were downloaded from the Cancer Genome Atlas (TCGA) database and the immune-related genes were obtained from the IMMPORT database ( http://www.immport.org/ ); then, the differentially expressed immune genes were screened out. Based on these genes, an immune gene prognosis model was constructed. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Further, the correlations among the risk score, clinicopathological characteristics, tumor microenvironment, and the prognosis of NSCLC were analyzed. A total of 193 differentially expressed immune genes related to NSCLC were screened based on the "wilcox.test" in R language, and Cox single factor analysis showed that 19 differentially expressed immune genes were associated with the prognosis of NSCLC (P < 0.05). After including 19 differentially expressed immune genes with P < 0.05 into the Cox multivariate analysis, an immune gene prognosis model of NSCLC was constructed (it included 13 differentially expressed immune genes). Based on the risk score, the samples were divided into the high-risk and low-risk groups. The Kaplan-Meier survival curve results showed that the 5-year overall survival rate in the high-risk group was 32.4%, and the 5-year overall survival rate in the low-risk group was 53.7%. The receiver operating characteristic model curve confirmed that the prediction model had a certain accuracy (AUC = 0.673). After incorporating multiple variables into the Cox regression analysis, the results showed that the immune gene prognostic risk score was an independent predictor of the prognosis of NSCLC patients. There was a certain correlation between the risk score and degree of neutrophil infiltration in the tumor microenvironment. The NSCLC immune gene prognosis assessment model was constructed based on bioinformatics methods, and it can be used to calculate the prognostic risk score of NSCLC patients. Further, this model is expected to provide help for clinical judgment of the prognosis of NSCLC patients.