Host stimulator of interferon genes is essential for the efficacy of anti-programmed cell death protein 1 inhibitors in non-small cell lung cancer.

The stimulator of interferon genes (STING) pathway is important for anticancer immune responses. However, the relative contributions of host and tumour STING in anti-programmed cell death protein 1 (anti-PD-1) inhibitor responses in non-small cell lung cancer (NSCLC) are unknown. STING expression in tumour and blood was associated with anti-PD-1 therapy in NSCLC patients; Moreover, loss of PD-1 inhibitor therapeutic potency was demonstrated in STING KO (knock out) splenocytes and STING KO mice. STING knock-down in tumour cells had no effect. STING on CD8+ T cells and host cells, not tumour cells, correlated with clinical effect of anti-PD-1 therapy in NSCLC patients. Finally, adoptive transfer of CD8+ T cells restored PD-1 inhibitor anticancer effects. STING in host cells but not in tumour cells mediates anti-PD-1 inhibitor responses in cancer immunotherapy and could be used to select advantageous NSCLC patients from immunotherapy.

Combination of computed tomography imaging-based radiomics and clinicopathological characteristics for predicting the clinical benefits of immune checkpoint inhibitors in lung cancer.

BACKGROUND: In this study, we tested whether a combination of radiomic features extracted from baseline pre-immunotherapy computed tomography (CT) images and clinicopathological characteristics could be used as novel noninvasive biomarkers for predicting the clinical benefits of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). METHODS: The data from 92 consecutive patients with lung cancer who had been treated with ICIs were retrospectively analyzed. In total, 88 radiomic features were selected from the pretreatment CT images for the construction of a random forest model. Radiomics model 1 was constructed based on the Rad-score. Using multivariate logistic regression analysis, the Rad-score and significant predictors were integrated into a single predictive model (radiomics nomogram model 1) to predict the durable clinical benefit (DCB) of ICIs. Radiomics model 2 was developed based on the same Rad-score as radiomics model 1.Using multivariate Cox proportional hazards regression analysis, the Rad-score, and independent risk factors, radiomics nomogram model 2 was constructed to predict the progression-free survival (PFS). RESULTS: The models successfully predicted the patients who would benefit from ICIs. For radiomics model 1, the area under the receiver operating characteristic curve values for the training and validation cohorts were 0.848 and 0.795, respectively, whereas for radiomics nomogram model 1, the values were 0.902 and 0.877, respectively. For the PFS prediction, the Harrell's concordance indexes for the training and validation cohorts were 0.717 and 0.760, respectively, using radiomics model 2, whereas they were 0.749 and 0.791, respectively, using radiomics nomogram model 2. CONCLUSIONS: CT-based radiomic features and clinicopathological factors can be used prior to the initiation of immunotherapy for identifying NSCLC patients who are the most likely to benefit from the therapy. This could guide the individualized treatment strategy for advanced NSCLC.

PD-L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real-world evidence.

BACKGROUND: Numerous studies have demonstrated that brain metastases patients may benefit from intracranial radiotherapy combined with immune checkpoint inhibitors (ICIs). However, it is unclear whether this treatment is effective for patients with small cell lung cancer brain metastases (SCLC-BMs). METHODS: We conducted a retrospective study by analyzing medical records of patients with SCLC-BMs from January 1, 2017 to June 1, 2022. Data related to median overall survival (mOS), median progression-free survival (mPFS), and intracranial progression-free survival (iPFS) were analyzed. RESULTS: A total of 109 patients were enrolled, of which 60 received WBRT and 49 received WBRT-ICI. Compared to the WBRT alone cohort, the WBRT-ICI cohort showed longer mOS (20.4 months vs. 29.3 months, p = 0.021), mPFS (7.9 months vs. 15.1 months, p < 0.001), and iPFS (8.3 months vs. 16.5 months, p < 0.001). Furthermore, WBRT-ICI cohort had a better response rate for both BMs. (p = 0.035) and extracranial diseases (p < 0.001) compared to those receiving WBRT alone. Notably, the use of WBRT before ICI was associated with longer mOS compared to the use of WBRT after ICI (23.3 months for the ICI-WBRT group vs. 34.8 months for the WBRT-ICI group, p = 0.020). CONCLUSION: Our results indicated that WBRT combined with immunotherapy improved survival in SCLC-BMs patients compared to WBRT monotherapy. Administering WBRT prior to ICI treatment is associated with improved survival outcomes compared to WBRT following ICI treatment, for patients with SCLC-BMs. These findings highlight the significance of conducting further prospective researches on combination strategies of intracranial radiotherapy and ICI in SCLC-BMs patients.

G-CSF improving combined whole brain radiotherapy and immunotherapy prognosis of non-small cell lung cancer brain metastases.

OBJECTIVE: To evaluate the therapeutic advantage of G-CSF to whole brain radiotherapy (WBRT) in combination with immunotherapy as a first-line treatment for non-small cell lung cancer (NSCLC) brain metastases (BMs). METHODS: In this retrospective study, 117 patients (37 in G-CSF group and 80 in no G-CSF group) who underwent first-line WBRT combined with immunotherapy were enrolled. Their survival, intracranial response, BM-related symptoms and toxicity were evaluated. RESULTS: The overall survival (OS) of patients in G-CSF group was significantly improved compared to patients no G-CSF group (median time: 14.8 vs 10.2 months; HR: 0.61, 95 % CI: 0.38-0.97, p = 0.035). However, there were no significant differences in intracranial responses between the two groups (p > 0.05). The G-CSF group exhibited a significantly higher rate of relief from BM-related symptoms compared to the no G-CSF group (91.7 % vs 59.5 %, p = 0.037). Cox proportional hazards regression analyses indicated that after-treatment ALC > 0.9 × 10^9/L (HR 0.57, 95 % CI 0.32-0.99, p = 0.046) and Hb > 110 g/dL (HR 0.41, 95 % CI 0.24-0.71, p = 0.001) were significant potential factors associated with extended OS. The addition of G-CSF was well tolerated and effectively reduced the incidence of neutropenia (0 % vs 5.0 %, p = 0.17). CONCLUSION: Integrating G-CSF with WBRT and immunotherapy as a first-line treatment for NSCLC-BMs has exhibited significant efficacy and favorable tolerability.

Flotillin-1 enhances radioresistance through reducing radiation-induced DNA damage and promoting immune escape via STING signaling pathway in non-small cell lung cancer.

Radiation resistance results in the recurrence and metastasis of non-small cell lung cancer (NSCLC) after radiotherapy. A major cause of radiation resistance is subversion of immune surveillance and clearance. Although our previous research has demonstrated that programmed death-ligand 1 (PD-L1) is responsible for radiation resistance in NSCLC, PD-L1 alone was not a reliable predictor of radiotherapy efficacy. For further exploration of the predictors of radiotherapy efficacy, which could add accuracy to the single biomarker - PD-L1, immunoprecipitation followed by mass spectrometry assay was performed to identify proteins that interact with PD-L1, and flotillin-1 (FLOT1) was detected as a candidate. However, the role of FLOT1 in radiation resistance in NSCLC is largely unknown. Here, we defined FLOT1 as a positive regulator of PD-L1 at the cell level, and the expression of PD-L1 was reduced following FLOT1 depletion. Furthermore, we found that the knockdown of FLOT1 impeded radiation-mediated cell migration and epithelial-mesenchymal transition process. Moreover, FLOT1 depletion enhanced radiation-induced DNA damage, thereby increasing the radiation lethality for NSCLC cells and promoting radiation-mediated tumor regression in animal models and patients with NSCLC. Furthermore, FLOT1 depletion-boosted DNA damage activated STING signaling pathway and promoted the production of CCL5 and CXCL10 that can drive CD8+ T lymphocytes chemotaxis, thereby reprogramming tumor immune microenvironment and triggering the antitumor immune response. Indeed, FLOT1 expression correlated with infiltration of immune cells in NSCLC tumor tissue samples. Taken together, our findings reported an unexplored role of FLOT1 in radiotherapy and also provided an evidence base for FLOT1 as a promising biomarker to predict the response to radiotherapy and a potential therapeutic target for enhancing radiotherapy effects.

Association of MUC19 Mutation With Clinical Benefits of Anti-PD-1 Inhibitors in Non-small Cell Lung Cancer.

Although anti-PD-1 inhibitors exhibit impressive clinical results in non-small cell lung cancer (NSCLC) cases, a substantial percentage of patients do not respond to this treatment. Moreover, the current recommended biomarkers are not perfect. Therefore, it is essential to discover novel molecular determinants of responses to anti-PD-1 inhibitors. We performed Whole Exome Sequencing (WES) in a cohort of 33 Chinese NSCLC patients. Patients were classified into the durable clinical benefit (DCB) and no durable benefit (NDB) groups. Infiltrating CD8+ cells in the tumor microenvironment (TME) were investigated by immunohistochemistry. We also used public datasets to validate our results. In our cohort, good clinical responses to anti-PD-1 inhibitors were more pronounced in younger patients with lower Eastern Cooperative Oncology Group (ECOG) scores and only extra-pulmonary metastasis. More importantly, we identified a novel MUC19 mutation, which was significantly enriched in DCB patients (P = 0.015), and MUC19-mutated patients had a longer progression-free survival (PFS) (hazard ratio = 0.3, 95% CI 0.1-0.9; P = 0.026). Immunohistochemistry results indicated that the MUC19 mutation was associated with increased infiltration by CD8+ T cells in the TME (P = 0.0313). When combining MUC19 mutation with ECOG scores and intra-pulmonary metastasis status, patients with more positive predictors had longer PFS (P = 0.003). Furthermore, MUC19 mutation was involved in immune responses and associated with a longer PFS in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Collectively, we identified that MUC19 mutations were involved in immune responses, and NSCLC tumors harboring mutated MUC19 exhibited good responses to anti-PD-1 inhibitors.

Evaluation of the Lung Immune Prognostic Index in Non-Small Cell Lung Cancer Patients Treated With Systemic Therapy: A Retrospective Study and Meta-Analysis.

The lung immune prognostic index (LIPI) has been shown to be an important prognostic marker for various tumors. However, the prognostic value of LIPI among non-small cell lung cancer (NSCLC) patients treated with systemic therapy remains controversial. We aimed to evaluate survival status according to LIPI among NSCLC patients receiving different forms of systemic therapy at our institution. We also performed a meta-analysis of articles from PubMed and Embase to illustrate this question. For our cohort, we found that good LIPI was associated with better overall survival (OS) among 91 patients on immunotherapy, 329 patients on targeted therapy, and 570 patients on chemotherapy. For the meta-analysis, a total of eight studies with 8,721 patients were included. Pooled results showed that a higher LIPI (those with 1 or 2 factors) was associated with poor overall progression-free survival (PFS) (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45-1.71) and OS (HR, 2.01; 95% CI, 1.75-2.31). Subgroup analyses showed that a higher LIPI was related to poor survival among patients prescribed different systemic therapies: immunotherapy (OS HR, 2.50; 95% CI, 1.99-3.13; PFS HR, 1.77; 95% CI, 1.56-2.01), chemotherapy (OS HR, 1.58; 95% CI, 1.34-1.86; PFS HR, 1.38; 95% CI, 1.23-1.55), and targeted therapy (OS HR; 2.15, 95% CI, 1.57-2.96; PFS HR, 1.60; 95% CI, 1.25-2.06). The study shows that the LIPI is a clinically significant prognostic factor for NSCLC patients receiving systemic therapy. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420209009.

Serum Exosomal miRNA Might Be a Novel Liquid Biopsy to Identify Leptomeningeal Metastasis in Non-Small Cell Lung Cancer.

PURPOSE: The survival time of patients with leptomeningeal metastasis (LM) of lung cancer is very short, and the clinical characteristics of LM are varied, making the clinical diagnosis difficult. At present, a positive CSF fluid (CSF) cytology result remains the gold standard for diagnosing LM in lung cancer; however, the process of collecting CSF is traumatic and far less convenient than blood collection. With the development in technology, an increasing number of studies prefer to use liquid biopsy to diagnose or predict the occurrence of the disease. Therefore, we aimed to explore whether serum exosomal miRNA can replace miRNA from CSF to identify or predict the occurrence of LM. PATIENTS AND METHODS: Herein, four pairs of serum and CSF samples were collected at four different time points from a patient with LM from non-small cell lung cancer (NSCLC). Serum and CSF exosomes were extracted. Western blot (CD63, TSG101) and electron microscope analyses were used to verify exosome extraction, after which exosomal miRNA sequencing was performed. Next, exosomal miRNA from serum and CSF samples from seven patients with LM and 30 patients without LM were collected for validation. RESULTS: Sequencing results of serum exosomal miRNA and CSF exosomal miRNA showed that there were 44 exosomal miRNAs stably co-expressed at four different time points. Then, three common miRNAs related to LM were found (hsa-miR-483-5p, hsa-miR-423-5p, and hsa-miR-342-5p). Subsequently, exosomal miRNA was extracted from serum and CSF samples from seven patients with LM and 30 patients without LM for verification, and the expression of these exosomal miRNA was detected. The results showed that miRNA-483-5p and miRNA-342-5p significantly differed in LM-/+ patients (P = 0.0142 and P = 0.0031, respectively), whereas miRNA-423-5p had no difference (P = 0.0921). Additionally, as the symptoms improved, the expression of these miRNAs decreased or remained stable. CONCLUSION: Serum exosomal miRNA (hsa-miR-483-5p, and hsa-miR-342-5p) may be involved in LM of lung cancer and may replace CSF to predict LM in NSCLC.

Clinical characteristics, laboratory abnormalities and CT findings of COVID-19 patients and risk factors of severe disease: a systematic review and meta-analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is an emerging pandemic of global public health concern. We aimed to summarize the characteristics of COVID-19 patients in the early stage of the pandemic and explore the risk factors of disease progression. METHODS: We conducted a systematic review with meta-analysis, searching three databases for studies published between January 1, 2020, and March 18, 2020. We used random-effects models to calculate the 95% confidence intervals of pooled estimated prevalence and the odds ratio between the severe and nonsevere cases. RESULTS: Ninety studies involving 16,526 COVID-19 patients were included. Hypertension (19.1%) and diabetes (9.5%) were the most common comorbidities. The most prevalent clinical symptoms were fever (78.4%), cough (58.5%), and fatigue (26.4%). Increased serum ferritin (74.2%), high C-reactive protein (73.3%), and high erythrocyte sedimentation rate (ESR) (72.2%) were the most frequently reported laboratory abnormalities. Most patients had bilateral lung involvement (82.2%) and showed peripheral (66.9%) and subpleural (62.1%) distribution, with multifocal involvement (73.1%). And the most common CT features were vascular enlargement (64.3%), ground-glass opacity (GGO) (60.7%), and thickened interlobular septa (55.1%). Respiratory failure was the most common complication (30.7%) and the overall case-fatality rate (CFR) was 4.2%. Moreover, male, history of smoking, and comorbidities might influence the prognosis. Most clinical symptoms such as fever, high fever, cough, sputum production, fatigue, shortness of breath, dyspnoea, and abdominal pain were linked to the severity of disease. Some specific laboratory indicators implied the deterioration of disease, such as leucocytosis, lymphopenia, platelet, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, creatinine, creatine kinase (CK), lactic dehydrogenase (LDH), C-reactive protein, procalcitonin (PCT), and D-dimer. Besides, the risk of bilateral pneumonia, consolidation, pleural effusion, and enlarged mediastinal nodes was higher in severe cases. CONCLUSIONS: Most COVID-19 patients have fever and cough with lymphopenia and increased inflammatory indices, and the main CT feature is GGO involved bilateral lung. Patients with comorbidities and worse clinical symptoms, laboratory characteristics, and CT findings tend to have poor disease progression.

Antibiotic exposure windows and the efficacy of immune checkpoint blockers in patients with cancer: a meta-analysis.

BACKGROUND: Immune checkpoint blockers (ICBs) improve the survival of patients with cancer, but primary or acquired drug resistance is inevitable. Intestinal microorganisms play an important role in immunotherapy and antitumor response, and antibiotic use can cause changes in intestinal microbial abundance and diversity. At present, the effects of antibiotic exposure on the anticancer activity of immunotherapy remain controversial. METHODS: We performed a meta-analysis of relevant studies retrieved from electronic databases to assess the effects of the time window of antibiotic exposure on the efficacy of immune checkpoint inhibitors (ICIs). In accordance with the definition of antibiotic use in different articles, the time window of antibiotic exposure was divided into three groups, namely, Groups 1 (antibiotic use within 2 months before or after ICI), 2 (antibiotic use before ICI), and 3 (antibiotic use anytime during ICI). RESULTS: After retrieval from the PubMed and the Embase databases, 39 cohorts were included. In group 1, progression-free survival [PFS; hazard ratio (HR) =1.81, 95% confidence interval (CI): 1.40-2.34] and overall survival (OS; HR =1.81, 95% CI: 1.43-2.28) were prolonged in patients without antibiotic use. In group 2, the subgroup analysis showed that antibiotic use had no effect on PFS (HR =0.90, 95% CI: 0.65-1.26) and OS (HR =1.53, 95% CI: 0.89-2.62) when the exposure window defined as 0-3 months. In Group 3, pooled results indicated that PFS (HR =0.78, 95% CI: 0.65-0.93) was prolonged in patients with antibiotic during immunotherapy, and no difference was observed in the OS data (HR =0.98, 95% CI: 0.78-1.24) between the patients with antibiotic and without antibiotic. CONCLUSIONS: Antibiotic use in shortly time (within before or after 2 months) around the initiation of immunotherapy was remarkably related to the efficacy of ICIs. A different scenario could be observed that during the long-term treatment of ICIs, the effect of antibiotic exposure seems to be eliminated.

Low-dose carboplatin reprograms tumor immune microenvironment through STING signaling pathway and synergizes with PD-1 inhibitors in lung cancer.

Although the combination of chemotherapy and immunotherapy is a hot topic in lung cancer, little is understood regarding the possible mechanisms behind their synergy. Moreover, safety is a major concern for clinicians while performing chemotherapy. Therefore, it is important to determine the appropriate dose and period of chemotherapy for combining it with immunotherapy, and investigate the underlying synergistic mechanism. Here, we showed that carboplatin can induce DNA damage and activate the canonical STING/TBK1/IRF3 pathway and non-canonical STING-NF-κB signaling complex. Further, low-dose carboplatin changed the "cold" tumor into a "hot" tumor via the signaling hub STING, augmenting CD8+ T-cell infiltration, increasing PD-L1 expression, and hence potentiating the anti-tumor effect of PD-1 inhibitors; importantly, there were no adverse effects. Furthermore, knocking down STING in tumor cells effectively reversed PD-L1 upregulation and STING pathway activation, and reduced the anti-tumor effect of low-dose carboplatin and carboplatin-PD-1 inhibitor combination. Our findings collectively reported a previously unexplored role of low-dose carboplatin targeting in the STING pathway and provided an economical, useful and safe option for improving the efficacy of PD-1 inhibitors in lung cancer.

Efficacy of rapid on-site evaluation for diagnosing pulmonary lesions and mediastinal lymph nodes: a systematic review and meta-analysis.

BACKGROUND: Although rapid on-site evaluation (ROSE) is gradually becoming an integral part of the modern Interventional Pulmonology, the clinical benefit of ROSE is still a matter of controversy. The objective of this meta-analysis was to clarify whether ROSE is effective in diagnosing pulmonary lesions and mediastinal lymph nodes, synchronously, to assess circumstances under which ROSE makes more sense. METHODS: MEDLINE and EMBASE were searched for studies comparing any outcome between ROSE and no-ROSE group in diagnosing pulmonary lesions and mediastinal lymph nodes. Statistical calculations were conducted using Review Manager, version 5.3, and Stata Release 12.0. Meta-analysis was completed using a random-effects model when I2≥50% or a fixed-effect otherwise. Heterogeneity was assessed by the I2-statistic test. Publication bias was assessed by the Begg's test. RESULTS: This Literature search yielded 27 studies altogether. The pooled risk difference of adequate rate was 0.12 [95% confidence intervals (CI): 0.07-0.16, I2=0%], the combined risk difference (RD) of diagnostic yield was 0.14 (95% CI: 0.09-0.18, I2=57%) while the pooled RD of sensitivity for malignancy was 0.10 (95% CI: 0.06-0.14, I2 =20%). Significant heterogeneity only existed in diagnostic yield (I2=57%, P=0.001). Further subgroup analysis documented a higher increase in diagnostic yield when sampling solid pulmonary lesions than sampling hilar/mediastinal lymph nodes 0.16 (95% CI: 0.12-0.20, I2=0%) versus 0.08 (95% CI: 0.04-0.13, I2=10%) and when applied to patients with suspected/diagnosed lung cancer than unselected patients 0.12 (95% CI: 0.06 to 0.18) versus 0.11 (95% CI: -0.07 to 0.28). CONCLUSIONS: ROSE is a useful technology in diagnosing pulmonary lesions and mediastinal lymph nodes, especially when sampling solid pulmonary lesions or applied to patients with suspected lung cancer.

Zebrafish Xenograft Model of Human Lung Cancer for Evaluating Osimertinib Resistance.

About half of NSCLC patients with EGFR mutation had secondary mutation T790M after treatment with a first-generation tyrosine kinase inhibitor (TKI), Gefitinib. The third-generation of EGFR-TKI Osimertinib is suitable for patients with EGFR mutation and T790M mutation. However, drug screening for NSCLC patients after the emergence of acquired resistance has become a difficult problem for clinicians. In this study, we established drug-resistant cell lines of Gefitinib and Osimertinib to evaluate cell proliferation in vitro. And we investigated the inhibitory effect of different drug concentration gradients on cancer cells. Zebrafish with high homology to human genes were selected as xenotransplantation models to compare the effects of different concentrations of Osimertinib on the proliferation and angiogenesis of zebrafish tumors after transplantation of different lung cancer cell lines. It was confirmed that Osimertinib could inhibit the proliferation of tumor cells with EGFR mutation and T790M resistance mutation in zebrafish, which was consistent with the clinical research conclusion.