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

Abstract

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 to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues. Unsupervised clustering based on numbers and percentages of 30 TIL types classified adenocarcinoma (LUAD) and squamous cell carcinoma (LUSQ) into the cold, myeloid cell-dominant, and CD8+ T cell-dominant subtypes. These were significantly correlated with patient prognosis; the myeloid cell subtype had worse outcomes than the others. Integrated genomic and transcriptomic analyses, including RNA sequencing, whole-exome sequencing, T-cell receptor repertoire, and metabolomics of tumor tissue, revealed that immune reaction-related signaling pathways were inactivated, while the glycolysis and K-ras signaling pathways activated in LUAD and LUSQ myeloid cell subtypes. Cases with ALK and ROS1 fusion genes were enriched in the LUAD myeloid subtype, and the frequency of TERT copy-number variations was higher in LUSQ myeloid subtype than in the others. These classifications of NSCLC based on TIL status may be useful for developing personalized immune therapies for NSCLC.

Significance:

The precise TIL profiling classified NSCLC into novel three immune subtypes that correlates with patient outcome, identifying subtype-specific molecular pathways and genomic alterations that should play important roles in constructing subtype-specific immune tumor microenvironments. These classifications of NSCLC based on TIL status are useful for developing personalized immune therapies for NSCLC.

• 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
• Journal: Cancer research communications (Cancer Res Commun) Vol. 3 Issue 6 Pg. 1026-1040 (06 2023) ISSN: 2767-9764 [Electronic] United States
• PMID: 37377611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins

Topics

• Humans
• Carcinoma, Non-Small-Cell Lung (genetics)
• Lung Neoplasms (genetics)
• Protein-Tyrosine Kinases (metabolism)
• Lymphocytes, Tumor-Infiltrating
• Proto-Oncogene Proteins (metabolism)
• Signal Transduction (genetics)
• Tumor Microenvironment (genetics)