mechanistic-links-between-depression-lung-cancer-progression

Mechanistic Links Between Depression and Lung Cancer Progression: Therapeutic Implications of Antidepressants

Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality ...

Zhejiang Shuren University

Lung cancer is a global health problem with a high mortality, and the development of target therapy has led to a revolution in the treatment of lung cancer in recent years. Favorable efficacy and safety of icotinib have been demonstrated in patients with non-small cell lung cancer (NSCLC). Currently, minimal data are available to describe the long-term safety of icotinib in NSCLC patients.

Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study.

Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non-small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641).

Clonal Architecture of  Mutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study (NCT03059641).

Limited benefit population of immune checkpoint inhibitors makes it urgent to screen predictive biomarkers for stratifying the patients. Herein, we have investigated peripheral CD4 T cell signatures in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-1/PD-L1 treatments. It was found that the percentages of IFN-γ and IL-17A secreting naïve CD4 T cells (Tn), and memory CD4 T cells (Tm) expressing PD-1, PD-L1 and CTLA-4 were significantly higher in responder (R) than non-responder (NonR) NSCLC patients associated with a longer progression free survival (PFS). Logistic regression analysis revealed that the baseline IFN-γ-producing CD4 Tn cells and PD-1CD4 Tm cells were the most significant signatures with the area under curve (AUC) value reaching 0.849. This was further validated in another anti-PD-1 monotherapy cohort. Conversely, high percentage of CTLA-4CD4 Tm cells was associated with a shorter PFS in patients receiving anti-PD-L1 monotherapy. Our study therefore elucidates the significance of functional CD4 Tn and Tm subpopulations before the treatment in predicting the responses to anti-PD-1 treatment in Chinese NSCLC patients. The fact that there display distinct CD4 T cell signatures in the prediction to anti-PD-1 and anti-PD-L1 monotherapy from our study provides preliminary evidence on the feasibility of anti-PD-1 and anti-PD-L1 combination therapy for advanced NSCLC patients.

Peripheral CD4 T cell signatures in predicting the responses to anti-PD-1/PD-L1 monotherapy for Chinese advanced non-small cell lung cancer.

Emerging studies have demonstrated that microRNAs (miRNAs) play crucial roles in the carcinogenesis of many developing human tumors. However, the clinical significance and biological function of microRNA-3648 (miR-3648) in non-small cell lung cancer (NSCLC) have been largely undefined.

High miR-3648 expression and low APC2 expression are associated with shorter survival and tumor progression in NSCLC.

Non-small cell lung cancer (NSCLC) ranks first among cancer death worldwide. Despite efficacy and safety priority, targeted therapy only benefits ∼30% patients, leading to the unchanged survival rates for whole NSCLC patients. Metabolic reprogramming occurs to offer energy and intermediates for fuelling cancer cells proliferation. Thus, mechanistic insights into metabolic reprogramming may shed light upon NSCLC proliferation and find new proper targets for NSCLC treatment. Herein, we used loss- and gain-of-function experiments to uncover that highly expressed aldo-keto reductase family1 member C1 (AKR1C1) accelerated NSCLC cells proliferation via metabolic reprogramming. Further molecular profiling analyses demonstrated that AKR1C1 augmented the expression of hypoxia-inducible factor 1-alpha (HIF-1α), which could drive tumour metabolic reprogramming. What's more, AKR1C1 significantly correlated with HIF-1α signaling, which predicted poor prognosis for NSCLC patients. Collectively, our data display that AKR1C1 reprograms tumour metabolism to promote NSCLC cells proliferation by activating HIF-1α. These newly acquired data not only establish the specific role for AKR1C1 in metabolic reprogramming, but also hint to the possibility that AKR1C1 may be a new therapeutic target for NSCLC treatment.

AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming.

Hypophysitis induced by programmed cell death 1 protein (PD-1) immune checkpoint inhibitors is rare and poorly described. We report three patients with non-small cell lung cancer who developed hypophysitis after anti-PD-1 immunotherapy.

Hypophysitis induced by anti-programmed cell death protein 1 immunotherapy in non-small cell lung cancer: Three case reports.

Erlotinib treatment can lead to skin diseases that drastically affected the quality of life of patients. Quercetin (Que), the active component in Xijiao Dihuang Decoction (XDD), was identified to improve inflammatory skin diseases. However, the mechanism of XDD treating erlotinib-induced cutaneous toxicity was not clear at the molecular level.

Xijiao Dihuang decoction relieves the erlotinib-induced dermatitis.

Diminished or lost Major Histocompatibility Complex class I (MHC-I) expression is frequently observed in tumors, which obstructs the immune recognition of tumor cells by cytotoxic T cells. Restoring MHC-I expression by promoting its transcription and improving protein stability have been promising strategies for reestablishing anti-tumor immune responses. Here, through cell-based screening models, we found that cediranib significantly upregulated MHC-I expression in tumor cells. This finding was confirmed in various non-small cell lung cancer (NSCLC) cell lines and primary patient-derived lung cancer cells. Furthermore, we discovered cediranib achieved MHC-I upregulation through transcriptional regulation. interferon regulatory factor 1 (IRF-1) was required for cediranib induced MHC-I transcription and the absence of IRF-1 eliminated this effect. Continuing our research, we found cediranib triggered STAT1 phosphorylation and promoted IRF-1 transcription subsequently, thus enhancing downstream MHC-I transcription. In vivo study, we further confirmed that cediranib increased MHC-I expression, enhanced CD8 T cell infiltration, and improved the efficacy of anti-PD-L1 therapy. Collectively, our study demonstrated that cediranib could elevate MHC-I expression and enhance responsiveness to immune therapy, thereby providing a theoretical foundation for its potential clinical trials in combination with immunotherapy.

Cediranib enhances the transcription of MHC-I by upregulating IRF-1.

Immunotherapies, mainly immune checkpoint inhibitors (ICIs), have revolutionized cancer treatment strategies over the past decade, but their limitations have limited clinical applications. Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy (ACT), which collects infiltrating lymphocytes at the tumor site and expands them in vitro to obtain TIL final products cloned by various T-cell receptors, subsequently reinfused TIL into the patient, which is effective for the treatment of solid tumors. The approval of Lifileucel for commercialization marks the success of TIL therapy. This review summarizes the current status of clinical trials of TIL treatment. In addition, it is suggested that the current research trend of TIL should focus on improving the survival time of TIL in vivo, reducing drug toxicity, and searching for prognostic markers. Finally, it is expected that TIL therapy can be applied to a more wide range of clinical treatments.

Current status and perspectives of clinical trials for tumor-infiltrating lymphocyte therapy.

β-sitosterol is a natural plant steroidal compound with anti-cancer properties against various tumors. This work explored the inhibitory effect of β-sitosterol on the progression of lung adenocarcinoma (LUAD) and further analyzed its targets. We applied network pharmacology to obtain the components and targets of Ganoderma spore powder. The biological functions of β-sitosterol and CHRM2 were studied using the homograft mouse model and a series of in vitro experiments involving quantitative reverse transcription polymerase chain reaction, western blot, CCK-8, flow cytometry, immunohistochemistry and immunofluorescence. The regulatory influence of β-sitosterol on the glycolysis pathway was validated by measuring glucose consumption and lactate production, as well as the extracellular acidification rate and oxygen consumption rate. We found that CHRM2 binds directly to β-sitosterol. In vitro, CHRM2 overexpression repressed the apoptosis rate and expression of apoptosis-related proteins in LUAD cells, and promoted glycolysis, while the addition of lonidamine attenuated the apoptosis-inhibiting effect conferred by CHRM2 overexpression. Furthermore, β-sitosterol hindered glycolysis as well as the growth of tumors in vitro and in vivo. CHRM2 overexpression reversed the effect of β-sitosterol on the biological behavior of LUAD cells. Our results emphasize that CHRM2 is a direct target of β-sitosterol in LUAD cells. β-sitosterol can repress the glycolysis pathway, exerting an anti-tumor effect. These findings provide new support for the use of β-sitosterol as a therapeutic agent for LUAD.

The active ingredient β-sitosterol in Ganoderma regulates CHRM2-mediated aerobic glycolysis to induce apoptosis of lung adenocarcinoma cells.

This prospective, observational study evaluated the real-world safety of osimertinib in a broad Chinese population with non-small cell lung cancer (NSCLC).

Article	Year
Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study. Journal of thoracic disease\| PubMed ID: 32274129	2020
Clonal Architecture of Mutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study (NCT03059641). Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 33188140	2021
Peripheral CD4 T cell signatures in predicting the responses to anti-PD-1/PD-L1 monotherapy for Chinese advanced non-small cell lung cancer. Science China. Life sciences\| PubMed ID: 33521853	2021
High miR-3648 expression and low APC2 expression are associated with shorter survival and tumor progression in NSCLC. Histology and histopathology\| PubMed ID: 34927228	2022
AKR1C1 promotes non-small cell lung cancer proliferation via crosstalk between HIF-1α and metabolic reprogramming. Translational oncology\| PubMed ID: 35429904	2022
Hypophysitis induced by anti-programmed cell death protein 1 immunotherapy in non-small cell lung cancer: Three case reports. World journal of clinical cases\| PubMed ID: 36338199	2022
Xijiao Dihuang decoction relieves the erlotinib-induced dermatitis. Experimental cell research\| PubMed ID: 36435221	2023
Cediranib enhances the transcription of MHC-I by upregulating IRF-1. Biochemical pharmacology\| PubMed ID: 38301967	2024
Current status and perspectives of clinical trials for tumor-infiltrating lymphocyte therapy. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico\| PubMed ID: 39078471	2025
The active ingredient β-sitosterol in Ganoderma regulates CHRM2-mediated aerobic glycolysis to induce apoptosis of lung adenocarcinoma cells. Genes & genetic systems\| PubMed ID: 39537174	2025
Safety of osimertinib in Chinese patients with non-small cell lung cancer: a multi-center, prospective, observational study. Future oncology (London, England)\| PubMed ID: 41164890	2025

Qiong Zhao

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