Abstract
BackgroundWe aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.MethodsTwo cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.ResultsSeven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.ConclusionsThere may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti–PD-1 antibody in BM.
Highlights
We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway
An intracranial response was assessed by brain gadolinium-enhanced magnetic resonance imaging (MRI), using Response Evaluation Criteria in Solid Tumors (RECIST) modified to allow target central nerve system lesions, 5 mm or larger in maximum diameter, and with up to five BMs permitted [24]
For fifteen patients with adenocarcinoma (75.0%), more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP+ (P = 0.016), and PD1+
Summary
We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. Immune checkpoint inhibitors (ICIs) have emerged as a promising new treatment in various cancer types. These drugs, including anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies and anti–programmed cell death-1 (anti-PD-1)/programmed cell death ligand-1 (PD-L1) antibodies, reactivate the anti-tumor immunity of T cells [10, 11]. The efficacy as a first-line treatment in metastatic non-small-cell lung cancer (NSCLC) was not evident yet, [12] nivolumab have been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic NSCLC and has become standard treatment in a second-line setting. The intracranial efficacy of ICIs is relatively unknown and has not yet been validated
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