Detection of identical T cell clones in peritumoral pleural effusion and pneumonitis lesions in a cancer patient during immune-checkpoint blockade

Abstract

// Kentaro Tanaka 1, * , Toyoshi Yanagihara 1, * , Yuki Ikematsu 1 , Hiroyuki Inoue 1 , Keiichi Ota 1 , Eiji Kashiwagi 2 , Kunihiro Suzuki 1 , Naoki Hamada 1 , Ario Takeuchi 2 , Katsunori Tatsugami 2 , Masatoshi Eto 2 , Kayo Ijichi 3 , Yoshinao Oda 3 , Kohei Otsubo 1 , Yasuto Yoneshima 1 , Eiji Iwama 1 , Yoichi Nakanishi 1 and Isamu Okamoto 1 1 Research Institute for Diseases of The Chest, Graduate School of Medical Sciences, Kyushu University, Higashu-Ku, Fukuoka 812-8582, Japan 2 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashu-Ku, Fukuoka 812-8582, Japan 3 Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Higashu-Ku, Fukuoka 812-8582, Japan * These authors have contributed equally to this work Correspondence to: Isamu Okamoto, email: okamotoi@kokyu.med.kyushu-u.ac.jp Keywords: immune-related adverse event; immune-checkpoint inhibitor; bronchoalveolar lavage fluid; next-generation sequencing; complementarity-determining region Received: April 05, 2018      Accepted: June 22, 2018      Published: July 17, 2018 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.