Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Two nomograms constructed for predicting the efficacy and prognosis of advanced non­small cell lung cancer patients treated with anti­PD­1 inhibitors based on the absolute counts of lymphocyte subsets.

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICIs) are at risk of considerable adverse events, and the ongoing struggle is to accurately identify the subset of patients who will benefit. Lymphocyte subsets play a pivotal role in the antitumor response, this study attempted to combine the absolute counts of lymphocyte subsets (ACLS) with the clinicopathological parameters to construct nomograms to accurately predict the prognosis of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1 inhibitors. METHODS: This retrospective study included a training cohort (n = 200) and validation cohort (n = 100) with aNSCLC patients treated with anti-PD-1 inhibitors. Logistic and Cox regression were conducted to identify factors associated with efficacy and progression-free survival (PFS) respectively. Nomograms were built based on independent influencing factors, and assessed by the concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve. RESULT: In training cohort, lower baseline absolute counts of CD3+ (P < 0.001) and CD4+ (P < 0.001) were associated with for poorer efficacy. Hepatic metastases (P = 0.019) and lower baseline absolute counts of CD3+ (P < 0.001), CD4+ (P < 0.001), CD8+ (P < 0.001), and B cells (P = 0.042) were associated with shorter PFS. Two nomograms to predict efficacy at 6-week after treatment and PFS at 4-, 8- and 12-months were constructed, and validated in validation cohort. The area under the ROC curve (AUC-ROC) of nomogram to predict response was 0.908 in training cohort and 0.984 in validation cohort. The C-index of nomogram to predict PFS was 0.825 in training cohort and 0.832 in validation cohort. AUC-ROC illustrated the nomograms had excellent discriminative ability. Calibration curves showed a superior consistence between the nomogram predicted probability and actual observation. CONCLUSION: We constructed two nomogram based on ACLS to help clinicians screen of patients with possible benefit and make individualized treatment decisions by accurately predicting efficacy and PFS for advanced NSCLC patient treated with anti-PD-1 inhibitors.

SIRPG expression positively associates with an inflamed tumor microenvironment and response to PD-1 blockade.

BACKGROUND: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. METHODS: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. RESULTS: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. CONCLUSION: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.

Integration of deep learning and habitat radiomics for predicting the response to immunotherapy in NSCLC patients.

BACKGROUND: The non-invasive biomarkers for predicting immunotherapy response are urgently needed to prevent both premature cessation of treatment and ineffective extension. This study aimed to construct a non-invasive model for predicting immunotherapy response, based on the integration of deep learning and habitat radiomics in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Independent patient cohorts from three medical centers were enrolled for training (n = 164) and test (n = 82). Habitat imaging radiomics features were derived from sub-regions clustered from individual's tumor by K-means method. The deep learning features were extracted based on 3D ResNet algorithm. Pearson correlation coefficient, T test and least absolute shrinkage and selection operator regression were used to select features. Support vector machine was applied to implement deep learning and habitat radiomics, respectively. Then, a combination model was developed integrating both sources of data. RESULTS: The combination model obtained a strong well-performance, achieving area under receiver operating characteristics curve of 0.865 (95% CI 0.772-0.931). The model significantly discerned high and low-risk patients, and exhibited a significant benefit in the clinical use. CONCLUSION: The integration of deep-leaning and habitat radiomics contributed to predicting response to immunotherapy in patients with NSCLC. The developed integration model may be used as potential tool for individual immunotherapy management.

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single-cell transcriptomic analysis: Implications for distinct immunotherapy outcomes.

BACKGROUND: Immune checkpoint blockade has emerged as a key strategy to the therapy landscape of non-small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level. METHODS: By integrative analysis of transcriptomic characterization of 38 NSCLC patients by single-cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients. RESULTS: LUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo-keto reductases, glutathione S-transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer-associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non-MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC. CONCLUSIONS: These comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype-specific treatment strategies.

Immune checkpoint inhibitor (ICI)-based treatment beyond progression with prior immunotherapy in patients with driver-gene negative advanced non-small cell lung cancer.

BACKGROUND: No definite conclusion has yet to be reached for immunotherapy beyond progression(IBP) of first-line immunotherapy as the second-line treatment for advanced NSCLC patients with negative driver genes. Therefore a retrospective study was conducted to evaluate the efficacy of IBP in this population and investigated whether the cycles best response and progressive mode of first-line immunotherapy could affect the results. PATIENTS AND METHODS: The clinical data of patients with advanced NSCLC whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy were retrospectively collected and the patients were assigned to the IBP and non-IBP groups. The overall survival (OS), progression-free survival (PFS) were evaluated between the two groups. The survival effects of cycles best response and progressive mode of first-line immunotherapy were also evaluated. RESULTS: Between January 2019 and January 2022, a total of 121 patients was evaluated as PD after first-line immunotherapy in our institution; 53 (43.8%) patients were included in the IBP group and 68 (56.2%) patients were included in the non-IBP group. The OS and PFS were no significantly different between the two groups in whole population. Further analysis revealed the OS was prolonged with the prolongation of first-line medication cycle. The median OS was 15.4m (15.4 vs 10.8 p=0.047) 16.1m (16.1 vs 10.8 p=0.039), 16.3m (16.3 vs 10.9 p=0.029) for patients with ≥4, ≥6, ≥8 cycles in first-line immunotherapy, respectively. The advantages of OS and PFS were also seen in the subgroup of PR (best response) and oligo progression of first-line immunotherapy. CONCLUSIONS: The clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But more cycles, PR as best response and oligo progression in first-line was benefit.

Patient-derived tumoroids and proteomic signatures: tools for early drug discovery.

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient's clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.

Prognostic implications of STK11 with different mutation status and its relationship with tumor-infiltrating immune cells in non-small cell lung cancer.

Background: Mutations in STK11 (STK11Mut) gene may present a negative impact on survival in Non-small Cell Lung Cancer (NSCLC) patients, however, its relationship with immune related genes remains unclear. This study is to unveil whether overexpressed- and mutated-STK11 impact survival in NSCLC and to explore whether immune related genes (IRGs) are involved in STK11 mutations. Methods: 188 NSCLC patients with intact formalin-fixed paraffin-embedded (FFPE) tissue available for detecting STK11 protein expression were included in the analysis. After immunohistochemical detection of STK11 protein, patients were divided into high STK11 expression group (STK11High) and low STK11 expression group (STK11Low), and then Kaplan-Meier survival analysis and COX proportional hazards model were used to compare the overall survival (OS) and progression-free survival (PFS) of the two groups of patients. In addition, the mutation data from the TCGA database was used to categorize the NSCLC population, namely STK11 Mutated (STK11Mut) and wild-type (STK11Wt) subgroups. The difference in OS between STK11Mut and STK11Wt was compared. Finally, bioinformatics analysis was used to compare the differences in IRGs expression between STK11Mut and STK11Wt populations. Results: The median follow-up time was 51.0 months (range 3.0 - 120.0 months) for real-life cohort. At the end of follow-up, 64.36% (121/188) of patients experienced recurrence or metastasis. 64.89% (122/188) of patients ended up in cancer-related death. High expression of STK11 was a significant protective factor for NSCLC patients, both in terms of PFS [HR=0.42, 95% CI= (0.29-0.61), P<0.001] and OS [HR=0.36, 95% CI= (0.25, 0.53), P<0.001], which was consistent with the finding in TCGA cohorts [HR=0.76, 95%CI= (0.65, 0.88), P<0.001 HR=0.76, 95%CI= (0.65, 0.88), P<0.001]. In TCGA cohort, STK11 mutation was a significant risk factor for NSCLC in both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) histology in terms of OS [HR=6.81, 95%CI= (2.16, 21.53), P<0.001; HR=1.50, 95%CI= (1.00, 2.26), P=0.051, respectively]. Furthermore, 7 IRGs, namely CALCA, BMP6, S100P, THPO, CGA, PCSK1 and MUC5AC, were found significantly overexpressed in STK11-mutated NSCLC in both LUSC and LUAD histology. Conclusions: Low STK11 expression at protein level and presence of STK11 mutation were associated with poor prognosis in NSCLC, and mutated STK11 might probably alter the expression IRGs profiling.

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system.

Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice. Methods: Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality. Results: The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs. Conclusion: These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression.

BACKGROUND: The presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer. RESULTS: Human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised. CONCLUSION: Collectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.

[Betulinic acid inhibits non-small cell lung cancer by repolarizing tumor-associated macrophages via mTOR signaling pathway].

The abnormal activation of the mammalian target of rapamycin(mTOR) signaling pathway in non-small cell lung cancer(NSCLC) is closely associated with distant metastasis, drug resistance, tumor immune escape, and low overall survival. The present study reported that betulinic acid(BA), a potent inhibitor of mTOR signaling pathway, exhibited an inhibitory activity against NSCLC in vitro and in vivo. CCK-8 and colony formation results demonstrated that BA significantly inhibited the viability and clonogenic ability of H1299, A549, and LLC cells. Additionally, the treatment with BA induced mitochondrion-mediated apoptosis of H1299 and LLC cells. Furthermore, BA inhibited the mobility and invasion of H1299 and LLC cells by down-regulating the expression level of matrix metalloproteinase 2(MMP2) and impairing epithelial-mesenchymal transition. The results demonstrated that the inhibition of mTOR signaling pathway by BA decreased the proportion of M2 phenotype(CD206 positive) cells in total macrophages. Furthermore, a mouse model of subcutaneous tumor was established with LLC cells to evaluate the anti-tumor efficiency of BA in vivo. The results revealed that the administration of BA dramatically retarded the tumor growth and inhibited the proliferation of tumor cells. More importantly, BA increased the ratio of M1/M2 macrophages in the tumor tissue, which implied the enhancement of anti-tumor immunity. In conclusion, BA demonstrated the inhibitory effect on NSCLC by repolarizing tumor-associated macrophages via the mTOR signaling pathway.

Immunotherapy in resectable NSCLC: Answering the question or questioning the answer?

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern-whether it's neoadjuvant, adjuvant, or a combination of both-is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation.

INTRODUCTION: Lung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear. METHODS: Firstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan-Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed. RESULTS: Firstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis. CONCLUSION: Our study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear. PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC. RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis. CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review.

Lung cancer is one of the most prevalent cancers globally, with non-small cell lung cancers constituting the majority. These cancers have a high incidence and mortality rate. In recent years, a growing body of research has demonstrated the intricate link between inflammation and cancer, highlighting that inflammation and cancer are inextricably linked and that inflammation plays a pivotal role in cancer development, progression, and prognosis of cancer. The Systemic Immunoinflammatory Index (SII), comprising neutrophil, lymphocyte, and platelet counts, is a more comprehensive indicator of the host's systemic inflammation and immune status than a single inflammatory index. It is widely used in clinical practice due to its cost-effectiveness, simplicity, noninvasiveness, and ease of acquisition. This paper reviews the impact of SII on the development, progression, and prognosis of non-small cell lung cancer.

BIBR1532 combined with radiotherapy induces ferroptosis in NSCLC cells and activates cGAS-STING pathway to promote anti-tumor immunity.

BACKGROUND: Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. METHODS: Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. RESULTS: Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. CONCLUSION: This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

The real-world treatment characteristic and efficacy of immune checkpoint inhibitors in non-small cell lung cancer: Data from a retrospective cohort study.

BACKGROUND: The efficacy and prognosis of immune checkpoint inhibitors (ICIs) remain unresolved issues. Here, we assessed the treatment characteristics and efficacy of ICIs in non-small cell lung cancer (NSCLC) using real-world data and evaluated the predictive value of factors, including programmed death-ligand 1 (PD-L1) expression, for the clinical outcome of ICIs in NSCLC. METHODS: Analyzed data was collected from hospitalized patients in the West China Hospital of Sichuan University between January 2017 and March 2023. The Kaplan-Meier method was utilized for analyzing real-world progression-free survival (rwPFS), while Cox regression models was employed to access the correlation between the efficacy of immunotherapy and sociodemographic characteristics, disease information, and characteristics of ICI treatment. RESULTS: A total of 545 patients were included in the retrospective study and characteristics of immunotherapy varied significantly among PD-L1 expression groups. The median rwPFS for the entire population was 9.76 months. Subgroup analyses revealed that patients with high PD-L1 expression, early TNM stage, first-line immunotherapy, EGFR wild-type and those who have not received radiotherapy and targeted therapy previously were more likely to have better rwPFS. Furthermore, multivariate Cox regression analyses identified PD-L1 expression, EGFR mutation status and previous radiotherapy as the most influential predictors of the response to ICI treatment. CONCLUSIONS: This study presents the real-world experience of Chinese NSCLC patients undergoing ICI treatment, offering guidance for clinical decision-making based on various patient conditions, preferences, and indications for ICIs, through the evaluation of immunotherapy efficacy and predictors in NSCLC patients.

[Advances in Pseudoprogression of Immune Checkpoint Inhibitors 
in Non-small Cell Lung Cancer].

The advent of immune checkpoint inhibitors (ICIs) has greatly improved the prognosis of advanced lung cancer patients, but can lead to pseudoprogression (PsP), which complicates clinical evaluation and management. PsP is manifested as temporary enlargement of the tumour or the appearance of new lesions, etc., and improvement in imaging occurs with continued treatment, mostly without worsening of clinical symptoms. Currently, there are still difficulties in the early diagnosis of PsP, and its occurrence mechanism is not yet clear, lacking good predictive factors and related biomarkers. This article reviews the current research status of PsP of ICIs in non-small cell lung cancer in order to provide helpful clinical strategies for oncologists using these drugs.
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