Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

Boyero, Laura; Sánchez-Gastaldo, Amparo; Alonso, Miriam; Noguera-Uclés, José Francisco; Molina-Pinelo, Sonia; Bernabé, Reyes

doi:10.3390/cancers12123729

Cited by 66 publications

(68 citation statements)

References 172 publications

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“…Furthermore, resistance to immunotherapy in lung cancer manifests as a lack of initial response or clinical benefit to therapy (primary resistance) or tumor progression after the initial period of response (acquired resistance). The primary resistance prevents the infiltration or function of immune cells in the TME, while Loss of T cell function may be a potential mechanism for acquired resistance to immunodetection point inhibitors ( 18 , 19 ). In addition, metabolic properties of non-small-cell lung cancers can reprogram stromal cells to induce resistance to EGFR inhibitors ( 11 , 20 ).…”

Section: Different Mechanisms Of Chemotherapy Resistance In Nsclcmentioning

confidence: 99%

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Luo

et al. 2021

Front. Oncol.

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Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

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Section: Different Mechanisms Of Chemotherapy Resistance In Nsclcmentioning

confidence: 99%

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Luo

et al. 2021

Front. Oncol.

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“…Computational Analysis of REsistance (CARE) is a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens ( Jiang et al, 2018 ). Previous studies have confirmed that the efficacy of immunotherapy is strongly influenced by the composition and abundance of immune cells in the TME ( Boyero et al, 2020 ).…”

Section: Introductionmentioning

confidence: 77%

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

Liu

et al. 2021

Front. Genet.

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A growing amount of evidence has suggested the clinical importance of stromal and immune cells in the liver cancer microenvironment. However, reliable prognostic signatures based on assessments of stromal and immune components have not been well-established. This study aimed to identify stromal-immune score–based potential prognostic biomarkers for hepatocellular carcinoma. Stromal and immune scores were estimated from transcriptomic profiles of a liver cancer cohort from The Cancer Genome Atlas using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm. Least absolute shrinkage and selection operator (LASSO) algorithm was applied to select prognostic genes. Favorable overall survivals and progression-free interval were found in patients with high stromal score and immune score, and 828 differentially expressed genes were identified. Functional enrichment analysis and protein–protein interaction networks further showed that these genes mainly participated in immune response, extracellular matrix, and cell adhesion. MMP9 (matrix metallopeptidase 9) was identified as a prognostic tumor microenvironment–associated gene by using LASSO and TIMER (Tumor IMmune Estimation Resource) algorithms and was found to be positively correlated with immunosuppressive molecules and drug response.

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“…Mechanistically, anti-PD-1 immunotherapy acts by breaking the interaction between PD-1 and PD-L1, which are responsible for the promotion of cancer immune evasion [23]. However, the application of anti-PD-1 immunotherapy in LUAD is limited by the primary or acquired drug resistance [23,24]. Recently, circRNAs have been reported to play vital roles in the tumorigenesis and progression of tumors [25,26].…”

Section: Discussionmentioning

confidence: 99%

CircRUNX1 Drives Immune Evasion and anti-PD1 Immunotherapy Resistance in Lung Adenocarcinoma by the miR-4739/PCSK9/MHC I Axis

Zhang

et al. 2021

Preprint

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Background: Lung adenocarcinoma (LUAD) is the commonest pathological subtype of lung-derived malignant tumor. Blocking the immune checkpoints interaction between programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) via naturalizing PD-1 or PD-L1 monoclonal antibody is proved to be a effective therapeutic method for drive gene negative LUAD. Dysregulation of circular RNA (circRNA) is a hallmark of cancer and has a critical role in the progression of cancers, including LUAD. However, the exact role of circular RUNX family transcription factor 1 (circRUNX1, hsa_circ_0002360) in LUAD remains unknown. Methods: The expression levels of circRUNX1, miR-4739, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA were examined by quantitative real-time polymerase chain reaction (qRT-PCR). PCSK9, histocompatibility complex I (MHC I), CD8, and Foxp3 protein expression was examined by immunohistochemistry (IHC) or western blot analysis. In vivo assay was carried out to determine the biological function of circRUNX1 on LUAD immune evasion in vivo. The binding relationship between miR-4739 and circRUNX1 or PCSK9 was predicted and verified by Starbase V3.0 online databases, dual-luciferase reporter assay, and RNA-pull down assay. Results: CircRUNX1 expression was frequently increased in LUAD tissues, and forced circRUNX1 expression was associated with poor prognosis, big tumor size, advanced stage, and resistance to anti-PD1 immunotherapy in LUAD patients. Functionally, circRUNX1 overexpression promoted LUAD immune evasion in vivo. In addition, our results demonstrated that circRUNX1 could sponge miR-4739, subsequently, upregulating the PCSK9 expression and promoting to LUAD immune evasion. Conclusion: circRUNX1 promoted cancer immune evasion and resistance to anti-PD1 immunotherapy by regulate miR-4739/PCSK9/MHC I axis in LUAD. Taken together, our findings indicate that circRUNX1 may be a promising therapeutic target for improve the anti-PD1 therapy effect in LUAD patients.

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Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

Cited by 66 publications

References 172 publications

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

CircRUNX1 Drives Immune Evasion and anti-PD1 Immunotherapy Resistance in Lung Adenocarcinoma by the miR-4739/PCSK9/MHC I Axis

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