PD-L1 as a biomarker in NSCLC: challenges and future directions

Mathew, Matthen; Safyan, Rachael A; Shu, Catherine A.

doi:10.21037/atm.2017.08.04

Cited by 41 publications

(28 citation statements)

References 29 publications

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“…6). The latter has a tremendously important clinical implication because patients' eligibility criteria PD-L1 blockade therapies are based on PD-L1 expression in their tumor biopsy samples (50). Our results thus demonstrate that TAM can modulate tumor metabolism as well as PD-L1 expression in tumors, compromising the tumor response to various anticancer therapies, including the latest immunotherapy.…”

Section: Discussionmentioning

confidence: 74%

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

et al. 2019

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Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18 fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFa to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed deathligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. Significance: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

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Section: Discussionmentioning

confidence: 74%

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

et al. 2019

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“…However, in this study, PD‐1/PD‐L1 expression levels were not significantly different between the 2 groups with and without EGFR mutations. Accumulated data now indicates that the PD‐L1 status alone is not a useful biomarker for the prediction of the efficacy of ICI …”

Section: Discussionmentioning

confidence: 99%

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

et al. 2019

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Recent clinical trials of non‐small cell lung cancer with immune checkpoint inhibitors revealed that patients with epidermal growth factor receptor (EGFR) mutations had more unfavorable outcomes compared with those with wild‐type EGFR. However, the underlying mechanism for the link between EGFR mutations and immune resistance remains unclear. We performed T cell receptor (TCR) repertoire analysis of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate the characteristics of TCR repertoires. We collected a total of 39 paired (normal and tumor) lung tissue samples (20 had EGFR mutations) and conducted TCR repertoire analysis as well as whole‐exome sequencing (WES) and transcriptome analysis. The TCR diversity index in EGFR‐mutant tumors was significantly higher than that in EGFR‐wild‐type tumors (median [range] 552 [162‐1,135] vs 230 [30‐764]; P < .01), suggesting higher T cell clonal expansion in EGFR‐wild‐type tumors than in EGFR‐mutant tumors. In WES, EGFR‐mutant tumors showed lower numbers of non‐synonymous mutations and predicted neoantigens than EGFR‐wild‐type tumors (P < .01, P = .03, respectively). The number of non‐synonymous mutations revealed a positive correlation with the sum of frequencies of the TCRβ clonotypes of 1% or higher in tumors (r = .52, P = .04). The present study demonstrates significant differences in TCR repertoires and the number of predicted neoantigens between EGFR‐mutant and wild‐type lung tumors. Our findings provide important information for understanding the molecular mechanism behind EGFR‐mutant patients showing unfavorable responses to immune checkpoint inhibitors.

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“…25 Second, each available validated IHC-assay uses different antibody clones, platforms, thresholds, and scoring algorithms. [26][27][28] The feasibility of harmonizing the clinical use of 4 commercial PD-L1 IHC assays has been studied in NSCLC, concluding that 3 of 4 assays are able to similarly detect tumor PD-L1 expression. 29,30 Nevertheless, interchanging assays and cutoffs leads to "misclassification" of PD-L1 status for 37% of patients, and this has important clinical consequences, as patients are potentially withheld from ICI treatment.…”

Section: Programmed Cell Death Ligand-1 Expression As a Marker For Immentioning

confidence: 99%

Programmed Cell Death-1/Ligand-1 PET Imaging

Verhoeff¹,

Heuvel

Herpen³

et al. 2020

PET Clinics

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Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have shown promising results in patients with various advanced stage solid tumors; however, response is limited to a subset of patients. Although the number of clinical studies with ICIs is rapidly increasing, there is still an unmet need for a robust biomarker to optimize response. PD-1/PD-L1 imaging using radiolabeled antibodies allows in vivo quantification of whole-body PD-1/PD-L1. Clinical PD-1/PD-L1 imaging can contribute to a better understanding of the dynamic complexity of PD-1/PD-L1 in the tumor microenvironment.

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PD-L1 as a biomarker in NSCLC: challenges and future directions

Cited by 41 publications

References 29 publications

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis

Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations

Programmed Cell Death-1/Ligand-1 PET Imaging

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