Dataset Information

[Basis of Tumor Microenvironment Relevant to Immunotherapies for Brain Metastases of NSCLC].

ABSTRACT: Brain is the most frequent site for distant metastases of non-small cell lung cancer (NSCLC). Brain metastasis (BM) is also the leading cause of disabilities and death in advanced NSCLC. In recent years, the application and effectiveness of small-molecule tyrosine kinase inhibitors has formed the basis for the treatment of NSCLC brain metastases with driver gene mutations. With the development of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors and relevant combination therapies, immunotherapy has become an important choice for non-classic oncogene addicted NSCLC BM patients. Also, the roles of relevant biomarkers are increasingly standing out. By reason of the particular immunopathological features of NSCLC brain metastases and its microenvironment, the aim of this review is to summarize relevant research progresses and provide more references for combination strategies of different therapeutic methods as well as the development of novel immunotherapies.?.

SUBMITTER: Lan Q

PROVIDER: S-EPMC6717868 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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[Basis of Tumor Microenvironment Relevant to Immunotherapies for Brain Metastases of NSCLC].

Lan Qing Q Ji Chunxia C Yao Yu Y

Zhongguo fei ai za zhi = Chinese journal of lung cancer 20190801 8

Brain is the most frequent site for distant metastases of non-small cell lung cancer (NSCLC). Brain metastasis (BM) is also the leading cause of disabilities and death in advanced NSCLC. In recent years, the application and effectiveness of small-molecule tyrosine kinase inhibitors has formed the basis for the treatment of NSCLC brain metastases with driver gene mutations. With the development of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors and ...[more]

PMID: 31451142

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Project description:BackgroundBrain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences.MethodsSeventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases.ResultsIn 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335-8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419-10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients.ConclusionsBoth temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.

Project description:BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+?SMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.

Project description:Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients. IMPLICATIONS FOR PRACTICE: Immunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.

Dataset Information

[Basis of Tumor Microenvironment Relevant to Immunotherapies for Brain Metastases of NSCLC].

Publications

[Basis of Tumor Microenvironment Relevant to Immunotherapies for Brain Metastases of NSCLC].

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