Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

Huang, Mofei; Xiong, Donghai; Pan, Jing; Zhang, Qi; Sei, Shizuko; Shoemaker, Robert H.; Lubet, Ronald A.; Montuenga, Luis M.; Wang, Yian; Slusher, Barbara S.; You, Ming

doi:10.1002/advs.202105885

Cited by 35 publications

(27 citation statements)

References 56 publications

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“…Targeting the fatty acid metabolizing enzyme Stearoyl-CoA desaturase-1 (SCD1) combined with anti-PD-1 also have a synergistic anti-tumor effect, by reducing Wnt/β-catenin signaling and promoting DCs recruitment ( 218 ). Although some studies showed promising results, there are still many challenges, such as the double-edged impact of glutaminase antagonism on T cell ( 167 , 219 , 220 ). The combination of IDO inhibitors with ICIs did not provide clinical benefit for patients ( 221 ).…”

Section: Firing Up the Cold Tumor: Strategies Overviewmentioning

confidence: 99%

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Zhou

Zhao

et al. 2023

Front. Immunol.

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Immune checkpoint inhibitors (ICIs) in the form of anti-CTLA-4 and anti-PD-1/PD-L1 have become the frontier of cancer treatment and successfully prolonged the survival of patients with advanced non-small cell lung cancer (NSCLC). But the efficacy varies among different patient population, and many patients succumb to disease progression after an initial response to ICIs. Current research highlights the heterogeneity of resistance mechanisms and the critical role of tumor microenvironment (TME) in ICIs resistance. In this review, we discussed the mechanisms of ICIs resistance in NSCLC, and proposed strategies to overcome resistance.

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Section: Firing Up the Cold Tumor: Strategies Overviewmentioning

confidence: 99%

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Zhou

Zhao

et al. 2023

Front. Immunol.

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“…The growth of UN680 L858R/T790M or UN680 tumors was measured every four to six days by a digital caliper. Tumor volumes were calculated using the formula: V = (length × width × width)/2 (27).…”

Section: Construction Of Lung Cancer Cell Lines With L858r Plasmids O...mentioning

confidence: 99%

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention

et al. 2023

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Epidermal growth factor receptor (EGFR) mutations occur in about 50% of lung adenocarcinomas in Asia and about 15% in the US. EGFR mutation-specific inhibitors have been developed and made significant contributions to controlling EGFR mutated non-small cell lung cancer. However, resistance frequently develops within 1 to 2 years due to acquired mutations. No effective approaches that target mutant EGFR have been developed to treat relapse following tyrosine kinase inhibitor (TKI) treatment. Vaccination against mutant EGFR is one area of active exploration. In this study, we identified immunogenic epitopes for the common EGFR mutations in humans and formulated a multi-peptide vaccine (Emut Vax) targeting the EGFR L858R, T790M, and Del19 mutations. The efficacy of the Emut Vax was evaluated in both syngeneic and genetic engineered EGFR mutation-driven murine lung tumor models with prophylactic settings, where the vaccinations were given before the onset of the tumor induction. The multi-peptide Emut Vax effectively prevented the onset of EGFR mutation-driven lung tumorigenesis in both syngeneic and genetically engineered mouse models (GEMMs). Flow cytometry and single-cell RNA sequencing were conducted to investigate the impact of Emut Vax on immune modulation. Emut Vax significantly enhanced Th1 responses in the tumor microenvironment and decreased suppressive Tregs to enhance anti-tumor efficacy. Our results show that multi-peptide Emut Vax is effective in preventing common EGFR mutation-driven lung tumorigenesis, and the vaccine elicits broad immune responses that are not limited to anti-tumor Th1 response.

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“…The inhibition of glutamine metabolism has been shown to sensitize many tumor cells to chemotherapy and thus overcome drug resistance. 11,12 While, in OS, little is known about how chemoresistance was regulated by glutamine metabolic reprogramming.…”

Section: Introductionmentioning

confidence: 99%

“…Glutamine metabolism provides energy for multiple cellular life activities and coordinates the biosynthesis of nucleosides, amino acids and lipids in cells. The inhibition of glutamine metabolism has been shown to sensitize many tumor cells to chemotherapy and thus overcome drug resistance 11,12 . While, in OS, little is known about how chemoresistance was regulated by glutamine metabolic reprogramming.…”

Section: Introductionmentioning

confidence: 99%

Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism

Ren,

Zhao,

Sun

et al. 2024

Intl Journal of Cancer

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Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three‐dimensional model of osteosarcoma constructed by seeding tumor cells (MG‐63 and MNNG/HOS Cl no. 5) within demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG‐63 and MNNG/HOS Cl no. 5 cell lines as compared to two‐dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted in a decrease in drug resistance of osteosarcoma, which could be restored by α‐ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.

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Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

Cited by 35 publications

References 56 publications

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention

Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism

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