Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments

• Published in: Cancer science Vol. 115; no. 6; pp. 1763 - 1777
• Main Authors: Fukuda, Hironori, Arai, Kosuke, Mizuno, Hideaki, Nishito, Yukari, Motoi, Noriko, Arai, Yasuhito, Hiraoka, Nobuyoshi, Shibata, Tatsuhiro, Sonobe, Yukiko, Kayukawa, Yoko, Hashimoto, Eri, Takahashi, Mina, Fujii, Etsuko, Maruyama, Toru, Kuwabara, Kenta, Nishizawa, Takashi, Mizoguchi, Yukihiro, Yoshida, Yukihiro, Watanabe, Shun‐ichi, Yamashita, Makiko, Kitano, Shigehisa, Sakamoto, Hiromi, Nagata, Yuki, Mitsumori, Risa, Ozaki, Kouichi, Niida, Shumpei, Kanai, Yae, Hirayama, Akiyoshi, Soga, Tomoyoshi, Tsukada, Keisuke, Yabuki, Nami, Shimada, Mei, Kitazawa, Takehisa, Natori, Osamu, Sawada, Noriaki, Kato, Atsuhiko, Yoshida, Teruhiko, Yasuda, Kazuki, Ochiai, Atsushi, Tsunoda, Hiroyuki, Aoki, Kazunori
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2024; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - immunology; Adenocarcinoma of Lung - pathology; Aged; Antigen-presenting cells; Biomarkers; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Cytotoxicity; Female; Flow cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomes; Glucose transporter; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis; Humans; Immune checkpoint inhibitors; Immune response; Immunotherapy; Inflammation; Leukocytes; Ligands; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Malignancy; Medical prognosis; Metabolomics; Middle Aged; molecular subtype; Mutation; Non-small cell lung carcinoma; Original; ORIGINAL ARTICLES; Patients; Phenotypes; Prognosis; Small cell lung carcinoma; Software; Squamous cell carcinoma; Statistical analysis; Transcriptomes; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; tumor‐infiltrating lymphocyte; lung cancer; tumor‐infiltrating lymphocyte; tumor microenvironment; immunotherapy; molecular subtype
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.16154

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non‐small‐cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi‐omics dataset, including tumor‐infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen‐presenting cells. The TRU subtype had low biological malignancy and “cold” tumor‐immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype. Our study shows the immune tumor microenvironment in different lung adenocarcinoma molecular subtypes: terminal respiratory unit and proximal proliferative had immunosuppressive microenvironment but differ in phenotypes, while the proximal inflammatory subtype has upregulated immune response. Understanding these traits may enable personalized immune therapy for lung cancer.