Clinical Efficacy and Future Prospects of Immunotherapy in Lung Cancer

Kinoshita, Tomonari; Terai, Hideki; Yaguchi, Tomonori

doi:10.3390/life11101029

Cited by 12 publications

(9 citation statements)

References 145 publications

(160 reference statements)

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“…However, their efficiency in monotherapy is still limited to 10–20% of unselected patients ( Hellmann et al, 2019 ; Herbst et al, 2020 ; Reck et al, 2016 ), and some initial responders eventually develop resistance. Therefore, combination therapies and optimization of sensitivity or resistance predictive biomarkers are emerging to further improve the efficacy of immunotherapy treatments (reviewed in Kinoshita et al [2021] and Grant et al [2021] ).…”

Section: Introductionmentioning

confidence: 99%

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

Valencia

Echepare

Teijeira

et al. 2022

Journal of Experimental Medicine

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Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.

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Section: Introductionmentioning

confidence: 99%

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

Valencia

Echepare

Teijeira

et al. 2022

Journal of Experimental Medicine

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“…For example, in clinical trials, cancer vaccines have not shown a positive effect on the survival of patients with NSCLC. On the other hand, conflicting data have been obtained on the effects of cytokine therapy on prognosis in lung cancer [ 21 , 22 ]. Immune checkpoint inhibitors are widely used in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…Immune checkpoint inhibitors are widely used in clinical practice. Thus, nivolumab, ipilimumab, and pembrolizumab are used in the complex therapy of lung cancer [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Cell Therapy with Human Reprogrammed CD8+ T-Cells Has Antimetastatic Effects on Lewis Lung Carcinoma in C57BL/6 Mice

Скурихин

Першина

Ермакова

et al. 2022

IJMS

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Using a model of Lewis lung carcinoma (LLC) in vitro and in vivo, we previously demonstrated increased antitumor activity in CD8+ T-cells reprogrammed with an MEK inhibitor and PD-1 blocker. In this follow-up study, we carried out the reprogramming of human CD8+ T-cells (hrT-cell) using the MEK inhibitor and PD-1 blocker and targeted LLC cells. The effects of hrT-cell therapy were studied in a mouse model of spontaneous metastasis of a solid LLC tumor. We found antimetastatic activity of hrT-cells, a decrease in the number of cancer cells and cancer stem cells in the lungs, and an increase in the number of T-cells in the blood (including effector T-cells). Thus, reprogramming of human CD8+ T-cells with an MEK inhibitor and PD-1 blocker with targeted training by tumor target cells is a potential platform for developing a new approach to targeted lung cancer therapy.

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“…Immunotherapies such as immune checkpoint inhibitors have proved to be highly effective in clinical trials. Nonetheless, many patients receiving immunotherapy will still develop immune resistance [ 5 ]. Intratumoral heterogeneity compromises the clinical efficacy of anticancer drugs, for instance, in the case of immunotherapy in cancer.…”

Section: Introductionmentioning

confidence: 99%

Intercellular Communication-Related Molecular Subtypes and a Gene Signature Identified by the Single-Cell RNA Sequencing Combined with a Transcriptomic Analysis

Guan

Cai

et al. 2022

Disease Markers

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Background. The tumor microenvironment (TME) of lung adenocarcinoma (LUAD) comprise various cell types that communicate with each other through ligand-receptor interactions. This study focused on the identification of cell types in LUAD by single-cell RNA sequencing (scRNA-seq) data and screening of intercellular communication-related genes. Methods. The Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo) provided the RNA-seq data of LUAD patients in the GSE149655, GSE31210, and GSE72094 datasets. Quality control of the scRNA-seq data in GSE149655 was performed by the Seurat package (http://seurat.r-forge.r-project.org) for identifying highly variable genes for principal component analysis (PCA) and cell clustering. The CellPhoneDB (http://www.cellphonedb.org) was used for filtering intercellular communication-related ligand-receptor pairs. According to ligand and receptor expressions, LUAD samples were clustered using ConsensusClusterPlus (https://www.bioconductor.org/packages/release/bioc/html/ConsensusClusterPlus). Additionally, the identification of prognosis-related ligand and receptor genes was conducted along with the development of a risk prediction model by the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Results. This study identified twelve cell types in 8170 cells of LUAD tissues along with 219 ligand and receptor genes. LUAD was classified into three different molecular subtypes, among which cluster 3 (C3) had the longest overall survival (OS) time and cluster (C1) had the shortest OS time. In comparison with the other two molecular subtypes, it was observed that C1 had a higher rate of somatic mutations and lower levels of infiltrating immune cells and immune scores. Ten genes were screened from the total ligand and receptor genes to construct a risk model, which showed a strong prediction power in the prognosis of patients with LUAD. Conclusion. The results of this study revealed cell types specific to LUAD, which were classified into different molecular subtypes according to intercellular communication-related genes. A novel prognostic risk model was developed in this study, providing new insights into prognostic assessment models for LUAD.

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Clinical Efficacy and Future Prospects of Immunotherapy in Lung Cancer

Cited by 12 publications

References 145 publications

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

Cell Therapy with Human Reprogrammed CD8+ T-Cells Has Antimetastatic Effects on Lewis Lung Carcinoma in C57BL/6 Mice

Intercellular Communication-Related Molecular Subtypes and a Gene Signature Identified by the Single-Cell RNA Sequencing Combined with a Transcriptomic Analysis

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