Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations

• DOI: 10.1158/2767-9764.crc-22-0415
• Publication Date: 2023-05-24T13:07:11Z
• Authors: Kazunori Aoki; Yukari Nishito; Noriko Motoi; Yasuhito Arai; Nobuyoshi Hiraoka; Tatsuhiro Shibata; Yukiko Sonobe; Yoko Kayukawa; Eri Hashimoto; Mina Takahashi; Etsuko Fujii; Takashi Nishizawa; Hironori Fukuda; Kana Ohashi; Kosuke Arai; Yukihiro Mizoguchi; Yukihiro Yoshida; Shun-ichi Watanabe; Makiko Yamashita; Shigehisa Kitano; Hiromi Sakamoto; Yuki Nagata; Risa Mitsumori; Kouichi Ozaki; Shumpei Niida; Yae Kanai; Akiyoshi Hirayama; Tomoyoshi Soga; Toru Maruyama; Keisuke Tsukada; Nami Yabuki; Mei Shimada; Takehisa Kitazawa; Osamu Natori; Noriaki Sawada; Atsuhiko Kato; Teruhiko Yoshida; Kazuki Yasuda; Hideaki Mizuno; Hiroyuki Tsunoda; Atsushi Ochiai
• Keywords: Immune checkpoint

Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness immunotherapy. This study examined the landscape NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected tissues. Unsupervised clustering based on numbers percentages 30 types classified adenocarcinoma (LUAD) squamous carcinoma (LUSQ) into cold, myeloid cell-dominant, CD8+ T cell-dominant subtypes. These were significantly correlated patient prognosis; subtype had worse outcomes than others. Integrated genomic transcriptomic analyses, including RNA sequencing, whole-exome T-cell receptor repertoire, metabolomics tissue, revealed that reaction-related signaling pathways inactivated, while glycolysis K-ras activated LUAD LUSQ Cases ALK ROS1 fusion genes enriched subtype, frequency TERT copy-number variations was higher classifications may be useful for developing personalized therapies NSCLC.The precise profiling novel three subtypes correlates outcome, identifying subtype-specific molecular alterations should play important roles constructing microenvironments. are NSCLC.