bims-meluca 2023-12-31 papers

Clin Exp Immunol. 2023 Dec 26. pii: uxad137. [Epub ahead of print]

FGL1 in plasma extracellular vesicles is correlated with clinical stage of lung adenocarcinoma and anti-PD-L1 response.

Yuchen Zhang, Kunpeng Zhang, Haoyu Wen, Di Ge, Jie Gu, Chunyi Zhang.

Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 (LAG3) which could inhibit antigen-mediated T cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma (LUSC). However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical TNM stage. Using lung cancer cell lines, we confirmed FGL1 can be detected on extracellular vesicles(EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both of animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and higher level indicated non-responsiveness to anti-PD-L1 immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker which plays an important role in predicting anti-PD-L1 immune therapy in LUAD, and suggests a new strategy in LUAD immunotherapy.

Keywords: EVs; FGL1; Immune therapy; LUAD; TNM stage

DOI: https://doi.org/10.1093/cei/uxad137

Mol Nutr Food Res. 2023 Dec 27. e2300577

Bckdk-Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia.

Li Chen, Hong Zhang, Mengyi Chi, Yaxian Wang, Xinting Zhu, Leng Han, Bo Xin, Run Gan, Yixin Tu, Xipeng Sun, Jin Lu, Jie Li, Jinlu Huang, Jianping Zhang, Yonglong Han, Cheng Guo, Quanjun Yang.

SCOPE: Branched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle-specific branched-chain α-keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting.
METHOD AND RESULTS: Muscle-specific Bckdk-cKO mice are generated through crossbreeding of Bckdkf/f mice with Myf5Cre mice. Lewis lung cancer (LLC) tumor transplantation is used to establish the cancer cachexia model. The occurrence of cancer cachexia is accelerated in the muscle-specific Bckdk-cKO mice after bearing LLC tumor. Wasting skeletal muscle is characterized by increased protein ubiquitination degradation and impaired protein synthesis. The wasting muscle gastrocnemius is mechanized as a distinct BCAA metabolic dysfunction. Based on the atrophy phenotype resulting from BCAA metabolism dysfunction, the optimized BCAA supplementation improves the survival of cancer cachexia in muscle-specific Bckdk-cKO mice bearing LLC tumors, and improves the occurrence of cancer cachexia. The mechanism of BCAA supplementation on muscle mass preservation is based on the promotion of protein synthesis and the inhibition of protein ubiquitination degradation.
CONCLUSIONS: Dysfunctional BCAA metabolism contributes to the inhibition of protein synthesis and increases protein degradation in the cancer cachexia model of muscle-specific Bckdk-cKO mice bearing LLC tumors. The reprogramming of BCAA catabolism exerts therapeutic effects by stimulating protein synthesis and inhibiting protein degradation in skeletal muscle.

Keywords: Bckdk; branch chain amino acid; cancer cachexia; metabolism; skeletal muscle

DOI: https://doi.org/10.1002/mnfr.202300577

Front Immunol. 2023 ;14 1305644

Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers.

Shiva Najjary, Willem de Koning, Johan M Kros, Dana A M Mustafa.

Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis.
Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors.
Results: Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings.
Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.

Keywords: brain metastasis; breast cancer; gene expression; lung adenocarcinoma; molecular mechanisms

DOI: https://doi.org/10.3389/fimmu.2023.1305644