bims-meluca 2024-08-18 papers

Cytotherapy. 2024 Jul 24. pii: S1465-3249(24)00801-6. [Epub ahead of print]

PD-1/PD-L1 interaction score and NKT-like cell infiltration predict immunotherapy efficacy in non-small cell lung cancer patients.

Jing Zhang, Dong Lin, Huihua Hu, Haipeng Xu.

OBJECTIVE: The currently available biomarkers are insufficient to accurately predict the immunotherapy response in patients. This work attempted to investigate effects of PD-1/PD-L1 interaction score combined with NKT-like cell infiltration level in tumor microenvironment on predicting immunotherapy efficacy.
METHODS: 24 non-small cell lung cancer (NSCLC) patients who underwent immunotherapy were analyzed using multiplex immunofluorescence to quantitatively assess positive cells of target biomarkers and their spatial localization. Correlation between PD-1/PD-L1 interaction score in combination with NKT-like cell infiltration level and immunotherapy response was analyzed. The predictive performance of two individual biomarkers and combined novel biomarkers in immunotherapy efficacy was assessed through receiver operating characteristic curve analysis. Relationships between these factors and patient survival prognosis were analyzed using Kaplan-Meier curves.
RESULTS: Among responders, PD-1/PD-L1 interaction score and NKT-like cell infiltration level were significantly higher than nonresponders (P < 0.05), and PD-1/PD-L1 interaction score and NKT-like cell infiltration level could effectively identify the population with immunotherapy response, with area under the curves (AUCs) of 0.7571 and 0.8643, respectively. Combination of the two had the best performance in predicting the efficacy of immunotherapy (AUC = 0.9070). High PD-1/PD-L1 interaction scores and high levels of NKT-like cell infiltration significantly improved progression-free survival (HR = 0.2544, P = 0.0053) and overall survival (HR = 0.2820, P = 0.0053) in patients.
CONCLUSIONS: Combination of PD-1/PD-L1 interaction score and NKT-like cell infiltration level had favorable performance in predicting immunotherapy response in NSCLC patients, contributing to accurately identify patients who may benefit from immunotherapy.

Keywords: NKT-like cells; efficacy; immunotherapy; interaction score; non-small cell lung cancer

DOI: https://doi.org/10.1016/j.jcyt.2024.07.010

Cell Insight. 2024 Oct;3(5): 100186

Deacetylation of GLUD1 maintains the survival of lung adenocarcinoma cells under glucose starvation by inhibiting autophagic cell death.

Qifan Hu, Longhua Sun, Zhujun Cheng, Lei Wang, Xiaorui Wan, Jing Xu, Junyao Cheng, Zuorui Wang, Yi Yuan, Keru Wang, Tianyu Han.

Enhanced glutamine catabolism is one of the main metabolic features of cancer, providing energy and intermediate metabolites for cancer progression. However, the functions of glutamine catabolism in cancer under nutrient deprivation need to be further clarified. Here, we discovered that deacetylation of glutamate dehydrogenase 1 (GLUD1), one of the key enzymes in glutamine catabolism, maintains the survival of lung adenocarcinoma (LUAD) cells under glucose starvation by inhibiting autophagic cell death. We found that glucose starvation increased GLUD1 activity by reducing its acetylation on Lys84 and promoted its active hexamer formation. Besides, deacetylation of GLUD1 induced its cytoplasmic localization, where GLUD1 was ubiquitinated in K63-linkage by TRIM21, leading to the binding of GLUD1 with cytoplasmic glutaminase KGA. These two effects enhanced glutamine metabolism both in mitochondria and cytoplasm, increased the production of alpha-ketoglutarate (α-KG). Meanwhile, cytoplasmic GLUD1 also interacted with p62 and prevented its acetylation, leading to the inhibition of p62 body formation. All these effects blocked autophagic cell death of LUAD cells under glucose starvation. Taken together, our results reveal a novel function of GLUD1 under glucose deprivation in LUAD cells and provide new insights into the functions of glutamine catabolism during cancer progression.

DOI: https://doi.org/10.1016/j.cellin.2024.100186

Nat Commun. 2024 Aug 10. 15(1): 6862

Identifying key circulating tumor DNA parameters for predicting clinical outcomes in metastatic non-squamous non-small cell lung cancer after first-line chemoimmunotherapy.

Haolun Ding, Min Yuan, Yaning Yang, Xu Steven Xu.

Circulating tumor DNA (ctDNA) provides valuable tumor-related information without invasive biopsies, yet consensus is lacking on optimal parameters for predicting clinical outcomes. Utilizing longitudinal ctDNA data from the large phase 3 IMpower150 study (NCT02366143) of atezolizumab in combination with chemotherapy with or without bevacizumab in patients with stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC), here we report that post-treatment ctDNA response correlates significantly with radiographic response. However, only modest concordance is identified, revealing that ctDNA response is likely not a surrogate for radiographic response; both provide distinct information. Various ctDNA metrics, especially early ctDNA nadirs, emerge as primary predictors for progression-free survival and overall survival, potentially better assessing long-term benefits for chemoimmunotherapy in NSCLC. Integrating radiographic and ctDNA assessments enhances prediction of survival outcomes. We also identify optimal cutoff values for risk stratification and key assessment timepoints, notably Weeks 6-9, for insights into clinical outcomes. Overall, our identified optimal ctDNA parameters can enhance the prediction of clinical outcomes, refine trial designs, and inform therapeutic decisions for first-line NSCLC patients.

DOI: https://doi.org/10.1038/s41467-024-51316-7

bioRxiv. 2024 Jul 30. pii: 2024.07.29.605645. [Epub ahead of print]

Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Aaron S Mansfield, Lindsay M LaFave, Tien Peng.

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identified senescent p16 Ink4a + cancer-associated fibroblasts with a secretory phenotype that promotes fatty acid uptake and utilization by aggressive lung adenocarcinoma driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16 Ink4a + cancer-associated fibroblasts also altered tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16 Ink4a + cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

DOI: https://doi.org/10.1101/2024.07.29.605645