The miRNA and PD-1/PD-L1 signaling axis: an arsenal of immunotherapeutic targets against lung cancer.

Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.

A mutational signature and significantly mutated driver genes associated with immune checkpoint inhibitor response across multiple cancers.

Immune checkpoint inhibitor (ICI) treatments dramatically prolong the survival outcomes of several advanced cancers. However, as multiple studies reported, only a subset of patients could benefit from the ICI treatment. In this study, we aim to uncover novel molecular biomarkers predictive of immunotherapy efficacy across multiple cancers. Pre-treatment somatic mutational profiles and immunotherapy clinical information were obtained from 1097 samples of multiple cancers, including melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), bladder carcinoma (BLCA), and head and neck squamous cell carcinoma (HNSCC). Mutational signatures, molecular subtypes, and significantly mutated genes (SMGs) were determined, and their connections with ICI response and outcome were also evaluated. We extracted a total of six mutational signatures across all samples. Among, a mutational signature featured by T > C substitutions was identified to associate with an ICI resistance. A molecular subtype determined based on mutational activities was connected with a significantly improved ICI response rate and outcome. Totaling 50 SMGs were identified, and we observed that patients with COL11A1 or COL4A6 mutations exhibited a superior ICI treatment efficacy than those without such mutations. In this study, we uncovered several novel molecular determinants of cancer immunotherapy response under a multiple-cancer setting, which provides clues for enrolling patients to receive immunotherapy and customizing personalized treatment strategies.

Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients.

Fatty acid synthase (FASN) acts as the central member in fatty acid synthesis and metabolism processes, which regulate oncogenic signals and tumor immunogenicity. To date, no studies have reported the connection of FASN mutations with ICI efficacy. In this study, from 631 melanoma and 109 NSCLC patients who received ICI treatments, we retrospectively curated multiomics profiles and ICI treatment data. We also explored the potential molecular biological mechanisms behind FASN alterations. In melanoma patients, FASN mutations were observed to associate with a preferable immunotherapeutic prognosis and response rate (both p < 0.01). These connections were further corroborated by the NSCLC patients (both p < 0.01). Further analyses showed that a favorable tumor immunogenicity and immune microenvironment were involved in FASN mutations. This work confirms the clinical immunotherapy implications of FASN mutation-mediated fatty acid metabolism and provides a possible indicator for immunotherapy prognosis prediction.

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies.

The Causes of Death and Their Influence in Life Expectancy of Children Aged 5-14 Years in Low- and Middle-Income Countries From 1990 to 2019.

Introduction: Although child and adolescent health is the core of the global health agenda, the cause of death and its expected contribution to life expectancy (LE) among those aged 5-14 are under-researched across countries, especially in low- and middle-income countries (LMICs). Methods: Death rates per 10 years age group including a 5-14-year-old group were calculated by the formula, which used the population and the number of deaths segmented by the cause of death and gender from the 2019 Global Burden of Disease (GBD) study. LE and cause-eliminated LE in 10-year intervals were calculated by using life tables. Results: In 2019, the global mortality rate for children and adolescents aged 5-14 years was 0.522 (0.476-0.575) per 1,000, and its LF was 71.377 years. In different-income regions, considerable heterogeneity remains in the ranking of cause of death aged 5-14 years. The top three causes of death in low-income countries (LICs) are enteric infections [0.141 (0.098-0.201) per 1,000], other infectious diseases [0.103 (0.073-0.148) per 1,000], and neglected tropical diseases and malaria [0.102 (0.054-0.172) per 1,000]. Eliminating these mortality rates can increase the life expectancy of the 5-14 age group by 0.085, 0.062, and 0.061 years, respectively. The top three causes of death in upper-middle income countries (upper MICs) are unintentional injuries [0.066 (0.061-0.072) per 1,000], neoplasm [0.046 (0.041-0.050) per 1,000], and transport injuries [0.045 (0.041-0.049) per 1,000]. Eliminating these mortality rates can increase the life expectancy of the 5-14 age group by 0.045, 0.031, and 0.030 years, respectively. Conclusion: The mortality rate for children and adolescents aged 5-14 years among LMICs remains high. Considerable heterogeneity was observed in the main causes of death among regions. According to the main causes of death at 5-14 years old in different regions and countries at different economic levels, governments should put their priority in tailoring their own strategies to decrease preventable mortality.

An aging-related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma.

Aging has been demonstrated to play vital roles in the prognosis and treatment efficacy of cancers, including lung adenocarcinoma (LUAD). This novel study aimed to construct an aging-related risk signature to evaluate the prognosis and immunogenicity of LUAD. Transcriptomic profiles and clinical information were collected from a total of 2518 LUAD patients from 12 independent cohorts. The risk signature was developed by combining specific gene expression with the corresponding regression coefficients. One cohort treated with the immune checkpoint inhibitor (ICI) was also used. Subsequently, a risk signature was developed based on 21 aging-related genes. LUAD patients with low-risk scores exhibited improved survival outcomes in both the discovery and validation cohorts. Further immunology analysis revealed elevated lymphocyte infiltration, decreased infiltration of immune-suppressive cells, immune response-related pathways, and favorable ICI predictor enrichment in the low-risk subgroup. Genomic mutation exploration indicated the enhanced mutation burden and higher mutation rates in significantly driver genes of TP53, KEAP1, SMARCA4, and RBM10 were enriched in patients with a low-risk signature. In the immunotherapeutic cohort, it was observed that low-risk aging scores were markedly associated with prolonged ICI prognosis. Overall, the estimated aging signature proved capable of evaluating the prognosis, tumor microenvironment, and immunogenicity, which further provided clues for tailoring prognosis prediction and immunotherapy strategies, apart from promoting individualized treatment plans for LUAD patients.

Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma.

Recent studies have demonstrated the role of Nod-like receptor protein 3 (NLRP3) inflammasome in promoting melanoma progression. Immune checkpoint inhibitors (ICI) treatment dramatically extended the survival outcomes for advanced melanoma patients. Nevertheless, immunologic and immunotherapy implications of NLRP3 mutations in melanoma were obscure. Herein, we utilized publicly genomic data of 750 melanoma patients to explore the association of NLRP3 mutations with immunologic and genomic features. In addition, we curated 336 advanced/metastatic melanoma patients treated with ICI agents from 6 published studies to analyze the response rate and survival outcome in relation to NLRP3 mutations. We observed that patients with NLRP3 mutations had a significantly higher tumor mutation burden (P < 0.001) and neoantigen burden (P < 0.001). Moreover, significantly lower tumor heterogeneity (P = 0.048) and purity (P = 0.022) were also observed in this mutated subgroup. Elevated infiltration of immune-response cells, decreased enrichment of immune-suppressive cells, and immune response-related circuits were markedly enriched in patients with NLRP3 mutations. In the pooled ICI-treated cohort, NLRP3 mutations were linked with the higher response rate (P = 0.031) and preferable survival outcome (P = 0.006). NLRP3 mutations were identified to associate with the elevated mutational burden, favorable immune infiltration, and preferable ICI efficacy. Findings derived from our study suggest that NLRP3 mutations may serve as a potential biomarker for evaluating melanoma immunotherapy response.

Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma.

Background: Immune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy. Methods: We comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously. Results: We identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45-0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10-1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11-1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, p < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23-0.87, p = 0.017). Conclusion: We uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.

Epidemic of chronic diseases and the related healthy lifestyle interventions in rural areas of Shandong Province, China.

BACKGROUND: There were amounts of previous studies on chronic diseases, but few studies on the prevalence of chronic disease and the healthy lifestyle intervention in recent years, China. This study aimed to investigate the prevalence of chronic disease and the implementation of healthy lifestyle intervention in rural areas of China, so as to put forward health promotion measures to control the chronic diseases effectively. METHOD: A large cross-sectional study (N = 2168) on community diagnosis and chronic disease was carried out in Shandong province, China. The chronic disease questionnaire and the healthy lifestyle intervention questionnaires were recruited to survey the chronic diseases and the implementation of healthy lifestyle intervention. Physical examination and biochemical indicators examination were carried out by the medical staffs and clinical laboratory. RESULTS: The current diagnosed prevalence of hypertension, diabetes, hyperlipidemia for total sample, female, male were 24.97, 24.6, 25.5, 7.60, 8.9, 6.0 and 40.27%, 45.9, 33.3% respectively in rural China. The one-year prevalence of myocardial infarction (MI) and stroke of the total sample, female, male were 1.06, 1.0, 1.1 and 2.09%, 2.2, 2.0% respectively. Healthy lifestyles interventions were not effective in rural China. The current active smoking rate and passive smoking rate were 25.68 and 42.65%. 27.86% of the population drunk alcohol within a month and 47.01% of them participated in the actions to control salt daily intake. Only 1.07 and 7.89% of the population participated in medium to high intensity physical exercises. CONCLUSIONS: The prevalence of common chronic diseases were still high and the implementation of healthy lifestyle intervention were not optimal in rural area, China. Challenges to prevent chronic diseases were still severe, so medical institutes, government and individuals would put forward effective strategies to reduce the prevalence and public health promotion project should be effectively strengthened.