Background: Immune-related adverse events (irAEs) may complicate the immune checkpoint inhibition (ICI) therapy. The effect of age on these irAEs is not elucidated. The aim of the study was to compare the occurrence of irAEs in different age groups.Methods: Patients with lung cancer receiving anti-programmed death- (ligand)1 (PD-(L)1) were selected from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Immune cell infiltration data set was obtained from TIMER 2.0 web server. The patients were stratified for age as follows: <65 year-old (young patients, YP), 65 to 75 year-old (middle aged patients, MP), ≥75 year-old (old patients, OP). The severity of irAEs was compared using logistic binary regression model. The distribution differences of immune cell infiltration were estimated using non-parametric tests.Results: Of all the 17,006 patients treated by anti-PD-(L)1, 7,355 were <65 (YP), 6,706 were 65–75 (MP), and 2,945 were ≥75 (OP). In general, we analyzed a total of 16 irAEs in this article and found that pulmonary toxicity was more frequent in OP (OP vs. YP: OR = 1.45, 95% CI: 1.28–1.64) and MP (MP vs. YP: OR = 1.38, 95% CI: 1.24–1.52), but hepatitis was less frequent in OP (OP vs. YP: OR = 0.56, 95% CI: 0.32–0.97) and MP (MP vs. YP: OR = 0.57, 95%CI: 0.38–0.85). Further analysis demonstrated that older patients showed less B cell, CD8⁺ T cell and myeloid dendritic cell infiltration than younger patients.Conclusions: Elderly patients exhibited higher incidences of pulmonary toxicity, while hepatitis was found at low incidence. Therefore, clinicians should carefully monitor comorbidities in elderly patients.

Tumor local and distant relapse recurrence after radiotherapy (RT) is one of the critical factors leading to poor prognosis. The effective antitumor effects of RT are dependent upon the participation of innate and adaptive components of the immune system. C5a/C5aR1 signaling can regulate antitumor immune effect in the tumor microenvironment (TME). Thus, exploring the changes and mechanism in the TME induced by RT-mediated complement activation may provide a novel perspective for reversing radioresistance. First, fractionated radiation of 8 Gy ×3 fractions were targeted at Lewis lung carcinoma (LLC) tumor-bearing female mice to measure the infiltration of CD8⁺ T cell and analyze the RNA sequencing (RNA-seq) in RT-recruited CD8⁺ T cells. Second, tumor growth was measured in LLC tumor-bearing mice treated with RT either with or without C5aR1 inhibitor to clarify the antitumor effect of RT combined with C5aR1 inhibitor. Third, we detected the expression of C5a/C5aR1 and their signaling pathways on radiated tumor tissues. Furthermore, we investigated the expression of C5a in tumor cells at different time points after different doses of RT. In our system, RT induced the increased infiltration of CD8⁺ T cells and local activation of complement C5a/C5aR. Concurrent administration of RT and blocking of C5aR improved radiosensitivity and tumor-specific immune response, which was reflected by high C5aR expression in CD8⁺ T cells. The AKT/NF-κB pathway was found to be an important signaling pathway in C5a/C5aR axis mediation by RT. RT promotes the release of C5a from tumor cells and leads to up-regulation of C5aR1 expression via the AKT/NF-κB pathway. Inhibition of the combination of complement C5a and C5aR could improve RT sensitivity. Our work provides evidence that the combination of RT and C5aR blockade opens a new window of opportunity to promote anti-tumor therapeutic effects in lung cancer.

With the widespread application of immune checkpoint inhibitor (ICI) combined with radiotherapy (RT) for the treatment of lung cancer, increasing attention has been paid to treatment-related pneumonitis. The effect of the treatment sequence on the incidence of pneumonitis remains unclear. We searched databases including PubMed, Embase, and ClinicalTrials.gov, meeting abstracts, and reference lists of relevant review articles for literature published on radio- and immunotherapy in lung cancer. Stata software (version 16.0) was used for meta-analysis. Data on the incidence of any grade and ≥ grade 3 pneumonitis was pooled using the random effects model. Bayesian network meta-analysis was used for arm-based pairwise comparisons. Subgroup analyses were performed to identify the potential influencing factors. Thirty-eight studies met our inclusion criteria. The network meta-analysis showed no significant difference between the incidence of pneumonitis in concurrent ICI with RT (concurrent arm) and RT followed by ICI (RT-first arm) (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.10-4.81). In the meta-analysis of single group rates, RT following ICI (ICI-first arm) exhibited higher incidence of any grade pneumonitis compared with concurrent- and RT-first arms, with 0.321 (95% CI: 0.260-0.386) for programmed cell death protein 1 (PD-1) inhibitors from clinical trials, and 0.480 (95% CI: 0.363-0.598) for PD-1 inhibitors from real-world retrospective data, respectively. No significant difference in the incidence of any grade and grade ≥ 3 pneumonitis was found between RT-first and concurrent arms. The ICI-first arm exhibited a higher incidence of pneumonitis, which needs to be further confirmed by follow-up studies.

Background: The prognostic roles of granulocyte-/granulocyte-macrophage colony-stimulating factor (G-/GM-CSF) and its receptors (CSFRs) from the genomic perspective remain controversial. The aim of our study was to evaluate their prognostic value in multiple cancer types by analyzing omics data. Methods: The omics data of G-/GM-CSF and receptors were obtained from the cBioportal database. Cutoff values were determined by X-tile. Overall survival (OS) was assessed by Kaplan–Meier curves. Differentially expressed genes (DEGs) and common regulated genes were analyzed using R software and Venny 2.1.0, while enrichment pathway analyses were performed by Metascape. Results: A comprehensive mRNA analysis was performed in 8,565 patients across 24 cancer types. The combination subgroup of CSF2 and its receptors with high expression and favorable prognosis was associated with the activation of immune-related pathways, while the subgroup with unfavorable prognosis was associated with the activation of inflammatory and cellular pathways. As for the combination subgroup of CSF3 and its receptor, the high expression and poor prognosis subgroup was accompanied by the activation of inflammation and signaling transduction pathways. Conclusions: The prognostic value of CSFs and CSFRs are cancer-type dependent. Therefore, personalized risk stratification based on CSF and CSFR pathway should be considered for cancer patients.

Although immunotherapy greatly extends overall survival (OS) of patients with extensive-stage small cell lung cancer (ES-SCLC), a number of patients develop immunotherapy resistance (IR). Patterns of failure in ES-SCLC are not clarified. Our study aims to explore the clinical pattern of IR and prognostic factors for these patients. The study was conducted from 117 ES-SCLC patients with immunotherapy between 2018 and 2022. Chi-square tests and Fishers' exact tests was used to explore failure patterns in different populations. Survival analyses of different progression patterns and subsequent treatment regimens were conducted by Kaplan–Meier curves and log-rank test. 86 (73.5%) patients experienced IR. The patients with smoking (never smoker vs. current or ex-smoker, 59.5 % vs. 81.3%, P = 0.010), liver metastasis (extrahepatic metastasis vs. intrahepatic metastasis, 73.6 % vs. 90.9%, P = 0.050), and distant metastasis status (no distant metastasis vs. distant metastasis, 39.1 % vs. 81.9%, P<0.001) were associated with IR rates. Liver progression had a lower incidence in 1st line immunotherapy (1st line vs. ≥2nd lines, 14.0 % vs. 41.7%, P = 0.004) and a higher incidence in multiple progression (multiple progression vs. Oligo-progression, 39.4 % vs. 17.0%, P = 0.021). Cranial (41.7 % vs. 16.1%, P = 0.012) and distant lymph node (16.7 % vs. 3.2%, P = 0.049) progression were the main failure model for acquired IR in comparison to primary IR. Patients with new lesion progression only (17.73 vs. 9.17 months, P = 0.013) and non-hepatic progression (14.23 vs. 11.67 months, P = 0.042) had a longer OS. Patients in cross-line immunotherapy after IR had a favourable prognosis (17.07 vs. 11.93 months, P = 0.007). The most common failure pattern of immunotherapy for ES-SCLC was lung and regional lymph node progression. Brain and liver progression were the most common extra thoracic failure sites for 1st line and 2nd and more lines immunotherapy, respectively. There was a higher probability of primary IR in 2 lines and above immunotherapy. Patients with new only progression site and cross-line rechallenge immunotherapy had a better prognosis.

Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X² = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X² = 6.475, P = .011). However, the "integrated factor", which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.