Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer

Zhou, Jie; Gong, Zhihua; Jia, Qingzhu; Wu, Yan; Yang, Zhenzhou; Zhu, Bo

doi:10.1016/j.bbrc.2018.03.053

Cited by 70 publications

(75 citation statements)

References 27 publications

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“…Mansfield et al [14] analyzed the expression of programmed cell death ligand 1 (PD-L1) in paired lung cancer and brain metastases from 73 patients using immunohistochemistry and showed that there was an agreement of PD-L1 expression in 86% of the paired specimens. However, Pinato et al's [15] and Zhou et al's [16] studies suggested a spatial and temporal heterogeneity in the expression of PD-L1 between isogeneic NSCLC and corresponding distant metastases, and they believed that such heterogeneity was significantly dependent on whether BM was synchronously diagnosed along with primary disease.…”

Section: Discussionmentioning

confidence: 99%

Characterization of genetic alterations in brain metastases from non‐small cell lung cancer

Liao

et al. 2018

FEBS Open Bio

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Brain metastasis (BM) is the primary contributor to mortality in non‐small cell lung cancer ( NSCLC ) patients. Although the findings of NSCLC genetic sequencing studies suggest the potential for personalizing therapeutic approaches, the genetic profiles and underlying mechanisms of BM progression remain poorly understood. Here, we investigated the genetic profiles of brain metastases from NSCLC in six patients with primary tumors and corresponding BM samples via whole exome sequencing and targeted panel sequencing. We have demonstrated considerable genetic heterogeneity between primary lung cancer and corresponding brain metastases specimens. High‐frequency mutations were found in NOTCH 2 , NOTCH 2 NL , FANCD 2 , EGFR , and TP 53 . Additionally, EGFR and TP 53 consistently exhibited high frequencies of mutation between primary tumors and corresponding brain metastases. The implication is that most of the genetic alterations may be acquired or lost during malignant progression, and the stable EGFR and TP 53 mutational status between paired primary tumors and metastatic sites confirms that most mutations detected on analysis of the primary tumor or metastases are sufficient for clinical decision‐making, and suggest there is no need to re‐biopsy recurrent tumors or metastases for most NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Characterization of genetic alterations in brain metastases from non‐small cell lung cancer

Liao

et al. 2018

FEBS Open Bio

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“…There is also a significant need to identify more predictive immune biomarkers in the CNS. Many series have shown increased density and/or number of CD3+ and/or CD8+ TILs in brain tumor specimens is correlated with improved survival ( 9 , 43 , 50 , 51 ). It is important to note that TIL density is lower in general in brain metastases and discordance in TIL density between primary tumors and brain metastases may be as high as 48% ( 51 , 52 ).…”

Section: Clinical Datamentioning

confidence: 99%

“…Many series have shown increased density and/or number of CD3+ and/or CD8+ TILs in brain tumor specimens is correlated with improved survival ( 9 , 43 , 50 , 51 ). It is important to note that TIL density is lower in general in brain metastases and discordance in TIL density between primary tumors and brain metastases may be as high as 48% ( 51 , 52 ). PD-L1 expression (≥ 1%) is present in ~ 25–30% of brain tumor specimens in some series, but it may be discordant from primary tumors in 30% of cases ( 9 , 51 , 53 ).…”

Section: Clinical Datamentioning

confidence: 99%

“…It is important to note that TIL density is lower in general in brain metastases and discordance in TIL density between primary tumors and brain metastases may be as high as 48% ( 51 , 52 ). PD-L1 expression (≥ 1%) is present in ~ 25–30% of brain tumor specimens in some series, but it may be discordant from primary tumors in 30% of cases ( 9 , 51 , 53 ). Discordance in TIL density or PD-L1 expression can be partially explained by temporal and spatial heterogeneity from biopsies taken at different time points and from different sites ( 51 ).…”

Section: Clinical Datamentioning

confidence: 99%

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Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease

Kamath

Kumthekar

2018

Front. Oncol.

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While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need.

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“…With the rapid development of surgery, chemotherapy, and radiotherapy, the control of extracranial lesions has significantly improved for lung cancer patients, but the incidence of BM has not declined. Survival after BM diagnosis remains poor with an average ranging from 1.5 to 9.5 months [ 3 , 4 ]. Therefore, it is essential to improve the prediction and prevention of BM.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylated-Akt overexpression is associated with a higher risk of brain metastasis in patients with non-small cell lung cancer

Jin

Yuan

et al. 2019

Biochemistry and Biophysics Reports

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Brain metastasis (BM) of non-small cell lung cancer (NSCLC) is relatively common and has a poor prognosis. Moreover, identifying which patients are more likely to develop BM is challenging. Akt, a serine/threonine-specific protein kinase, can be activated in various tumors, including lung cancer, and may be associated with poor prognosis. Here, we used immunohistochemistry to evaluate phosphorylated-Akt (p-Akt) expression in tumor tissues of 99 NSCLC patients. We also analyzed the genotype of the patients for two single nucleotide polymorphisms (SNPs) of the AKT1 gene, rs2498804 and rs2494732. We found that p-Akt expression differs between NSCLC patients and correlates with the risk of BM. Indeed, patients exhibiting medium to high p-Akt expression had a higher incidence of BM than those exhibiting low to no p-Akt expression (39% vs 16%). Our data also show that patients with the rs2498804 GT/GG and rs2494732 CT/TT variant genotypes were more likely to exhibit higher levels of p-Akt expression than those with the rs2498804 TT and rs2494732 CC variant genotypes (35% vs. 24% and 37% vs. 25%, respectively). Our results suggest that the level of expression of p-Akt, which may be affected by the AKT1 genotype, is correlated with the risk of BM. However, further studies are needed to establish p-Akt as a predictive marker for BM in NSCLC patients.

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Programmed death ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer

Cited by 70 publications

References 27 publications

Characterization of genetic alterations in brain metastases from non‐small cell lung cancer

Characterization of genetic alterations in brain metastases from non‐small cell lung cancer

Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease

Phosphorylated-Akt overexpression is associated with a higher risk of brain metastasis in patients with non-small cell lung cancer

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