Bulk and single-cell RNA sequencing reveal the contribution of laminin γ2 -CD44 to the immune resistance in lymphocyte-infiltrated squamous lung cancer subtype

Tingting Song; Ying Yang; Yilong Wang; Yinyun Ni; Yongfeng Yang; Li Zhang

Heliyon (May 2024)

Bulk and single-cell RNA sequencing reveal the contribution of laminin γ2 -CD44 to the immune resistance in lymphocyte-infiltrated squamous lung cancer subtype

Tingting Song,
Ying Yang,
Yilong Wang,
Yinyun Ni,
Yongfeng Yang,
Li Zhang

Affiliations

Tingting Song: Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China
Ying Yang: Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China
Yilong Wang: Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China
Yinyun Ni: Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China
Yongfeng Yang: Corresponding author. Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University Chengdu, 610041, China.; Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China
Li Zhang: Corresponding author.; Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China

Journal volume & issue: Vol. 10, no. 10
p. e31299

Abstract

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The high heterogeneity of lung squamous cell carcinomas (LUSC) and the complex tumor microenvironment lead to non-response to immunotherapy in many patients. Therefore, characterizing the heterogeneity of the tumor microenvironment in patients with LUSC and further exploring the immune features and molecular mechanisms that lead to immune resistance will help improve the efficacy of immunotherapy in such patients. Herein, we retrospectively analyzed the RNA sequencing (RNA-seq) data of 513 LUSC samples with other multiomics and single-cell RNA-seq data and validated key features using multiplex immunohistochemistry. We divided these samples into six subtypes (CS1–CS6) based on the RNA-seq data and found that CS3 activates the immune response with a high level of lymphocyte infiltration and gathers a large number of patients with advanced-stage disease but increases the expression of exhausted markers cytotoxic T-lymphocyte associated protein 4, lymphocyte-activation gene 3, and programmed death-1. The prediction of the response to immunotherapy showed that CS3 is potentially resistant to immune checkpoint blockade therapy, and multi-omic data analysis revealed that CS3 specifically expresses immunosuppression-related proteins B cell lymphoma 2, GRB2-associated binding protein, and dual-specificity phosphatase 4 and has a high mutation ratio of the driver gene ATP binding cassette subfamily A member 13. Furthermore, single-cell RNA-seq verified lymphocyte infiltration in the CS3 subtype and revealed a positive relationship between the expression of LAMC2-CD44 and immune resistance. LAMC2 and CD44 are epithelial-mesenchymal transition-associated genes that modulate tumor proliferation, and multicolor immunofluorescence validated the negative relationship between the expression of LAMC2-CD44 and immune infiltration. Thus, we identified a lymphocyte-infiltrated subtype (CS3) in patients with LUSC that exhibited resistance to immune checkpoint blockade therapy, and the co-hyperexpression of LAMC2-CD44 contributed to immune resistance, which could potentially improve immunological efficacy by targeting this molecule pair in combination with immunotherapy.

Published in Heliyon

ISSN: 2405-8440 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Science (General); Social Sciences: Social sciences (General)
Website: https://www.cell.com/heliyon/home

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