Abstract
Although immune-related adverse events (irAEs) of treatment with immune-checkpoint inhibitors may be due to cellular immunity mediated by T lymphocytes, their pathogenesis has remained unknown. Here we collected bronchoalveolar lavage fluid (BALF) from a cancer patient with nivolumab-induced pneumonitis and isolated mononuclear cells for next-generation sequencing of the complementarity-determining region of the T cell receptor (TCR) β chain. Mononuclear cells in peritumoral pleural effusion isolated from the patient were similarly analyzed, and the results obtained for the two specimens were compared. A substantial number of TCRβ clones in BALF were also identified among lymphocytes in the peritumoral pleural effusion. Such a correlation was not apparent between TCRβ clones in BALF and those in peripheral blood. Moreover, many tumor-associated clones with a read frequency of ≥0.10% were also present in BALF. Our data suggest that irAEs might be induced by drug-activated lymphocytes originating from tumor tissue. Deep sequencing will thus be indispensable for investigations of the immune-based pathogenesis of, and the development of optimal treatments for, irAEs.
Highlights
Immune-checkpoint inhibitors (ICIs) have shown marked efficacy in and improved the survival of individuals with various advanced cancers [1]
These observations suggested that the intrathoracic space reflected the peritumoral microenvironment and that the pleuritis was mediated by ICI-activated tumor-infiltrating lymphocytes (TILs) that had exited from the tumor sites [6]
According to an official American Thoracic Society clinical practice guideline, cellular analysis of bronchoalveolar lavage fluid (BALF) and examination of a high-resolution computed tomography (CT) scan are recommended to support a specific diagnosis of interstitial lung disease [10]
Summary
Immune-checkpoint inhibitors (ICIs) have shown marked efficacy in and improved the survival of individuals with various advanced cancers [1]. These drugs often trigger immune-related adverse events (irAEs) including pneumonitis. The presence of infiltrating T lymphocytes in organs affected by such irAEs has suggested that these events are due to cellular immunity mediated by T cells [2, 3, 4]. The immunologic mechanism responsible for irAEs has remained unclear, and their optimal treatment has yet to be established. Analysis of T cell receptor (TCR) clonality revealed that tumor-infiltrating lymphocytes (TILs) may have contributed to pathogenesis of the irAE
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