Abstract 2717: Antitumor effects are augmented in mouse models of interstitial-lung disease caused by immune-checkpoint inhibitors
Authors: Arita Masashi , Watanabe Satoshi , Yanagimura Naohiro , Mishina Yuko , Sato Miyuki , Shoji Satoshi , Ichikawa Kosuke , Kondo Rie , Tanaka Junta , Sakagami Takuro , Koya Toshiyuki , Kikuchi Toshiaki 
Published: August 2018

In recent years, cancer immunotherapy has been emerged as a major therapeutic modality in several malignancies. Immune-checkpoint inhibitors (ICI), such as anti-programmed death 1 (PD-1) / programmed death -ligand 1 (PD-L1) antibodies and anti-cytotoxic-T-lymphocyte associated protein-4 (CTLA-4) antibodies have demonstrated durable antitumor effects. In phase III trials, PD-1 / PD-L1 blockade therapies have shown better survival benefits compared to standard chemotherapies in patients with non-small lung cancer. However, the mechanisms of anti-PD-1 treatments have not been fully understood. Immune-checkpoint molecules play an important role to regulate autoimmune reactions by T cells. Thus, PD-1 / PD-L1 blockade therapy and anti-CTLA-4 treatment can cause immune-related adverse events including interstitial-lung disease (ILD). ILD is a serious and life threatening adverse event. On the other hand, better outcomes have been reported in lung cancer patients who developed ILD during anti-PD-1 treatment. These findings suggest that effector T cells attack similar antigens presented on both tumor cells and normal lung tissues. In order to elucidate the mechanisms of development of ILD and augmentation of anti-tumor effect by ICI, we established mouse model of ILD. In this study, C57BL/6J mice were injected intravenously with MCA 205 fibrosarcoma or B16 melanoma to make lung metastases. These mice were administered intraperitoneally with anti-PD-1 antibodies and/or anti-CTLA-4 antibodies. EGFR-TKI-ILD mice, which have been previously reported elsewhere, were also established to compare the pathological findings with those of ICI-induced ILD. Also, we administered lipopolysaccharide (LPS) intratracheally before injection of ICIs to test whether lung inflammation exacerbate ILD caused by ICIs. The infiltration of inflammatory cells and thickening of interstitial wall in the lung tissue were observed in mice treated with the combination of anti-CTLA-4 antibodies and anti-PD-1 antibodies. The antitumor effects of anti-PD-1 treatment against lung metastases were enhanced in mice which had ILD caused by anti-PD-1 antibodies and injury of bronchial epithelium. High density of infiltration of lymphocytes in tumor tissues was observed in ILD mice. Further study is warranted to determine effector cells which are responsible for establishment of ILD and augmentation of antitumor effects.

Citation Format: Masashi Arita, Satoshi Watanabe, Naohiro Yanagimura, Yuko Mishina, Miyuki Sato, Satoshi Shoji, Kosuke Ichikawa, Rie Kondo, Junta Tanaka, Takuro Sakagami, Toshiyuki Koya, Toshiaki Kikuchi. Antitumor effects are augmented in mouse models of interstitial-lung disease caused by immune-checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2717.