Chronic obstructive pulmonary disease alters the genetic landscape and tumor immune microenvironment in lung cancer patients

Qiurui Zhang; Xijia Feng; Weiting Hu; Chengqiang Li; Debin Sun; Zhao Peng; Shengzhou Wang; Hecheng Li; Min Zhou

doi:10.3389/fonc.2023.1169874

Chronic obstructive pulmonary disease alters the genetic landscape and tumor immune microenvironment in lung cancer patients

Front Oncol. 2023 Jun 14:13:1169874. doi: 10.3389/fonc.2023.1169874. eCollection 2023.

Authors

Qiurui Zhang^{1

2

3}, Xijia Feng⁴, Weiting Hu^{1

2

3}, Chengqiang Li⁴, Debin Sun⁵, Zhao Peng⁵, Shengzhou Wang⁵, Hecheng Li⁴, Min Zhou^{1

2

3}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China.
⁴ Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Genecast Biotechnology Co., Ltd., Wuxi, Jiangsu, China.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) and lung cancer are leading causes of morbidity and mortality worldwide. Studies have reported molecular alterations in patients with lung cancer and in patients with COPD. However, few investigation has been conducted on the molecular characteristics of lung cancer patients with COPD.

Materials and methods: We performed a retrospective cohort study that included 435 patients with pathologically confirmed lung cancer at the Ruijin Hospital. For patients with documented spirometry, Global Initiative for Chronic Obstructive Lung Disease criteria were used to define COPD. For patients without documented spirometry, chest computed tomography and other clinical information were used to define COPD. Tumor tissue DNA was extracted from formalin-fixed paraffin-embedded samples. DNA mutation analysis, multiplex immunohistochemistry (mIHC), calculation of tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), and predication of neoantigens were performed.

Results: Although SNV mutations in lung cancer patients with COPD (G1 group) were generally higher than those in lung cancer patients without COPD (G2 group), the difference in the number of mutations was insignificant between the two groups. Of the 35 mutated genes, the number of them was higher in G1 than in G2, except that of EGFR. PI3K-Akt signaling pathway was enriched from significantly different genes. While TMB and MATH levels were not significantly different, the tumor neoantigen burdenwas markedly higher in G1 than that in G2. The level of CD68+ macrophages was significant higher in the stroma and total areas in the G1 group than in G2 group. The level of CD8+ lymphocytes was markedly higher in the stroma and showed a clear tendency forhigher expression in the G1 group than inthe G2 group. No significant differences were observed for the level of programmed death-ligand 1+ (PD-L1+), programmed death 1+ (PD-1+), and CD68PD-L1 in the stroma, tumor and total areas.

Conclusion: Our study revealed different genetic aberrations and pathways, higher neoantigen burden, and higher level of CD68+ macrophages and CD8+ T lymphocytes in lung cancer patients with COPD. Our investigation implies that the existence of COPD should be considered and immunotherapy is a potential choice when treating lung cancer patients with COPD.

Keywords: PI3K-Akt signaling pathway; chronic obstructive pulmonary disease; genetic mutations; lung cancer; tumor immune microenvironment.

Grants and funding

This work was supported by the Grant of Shanghai Municipal Key Clinical Specialty (No. shslczdzk02202), Shanghai Top-Priority Clinical Key Disciplines Construction Project (No. 2017ZZ02014), Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases (No. 20dz2261100), Cultivation Project of Shanghai Major Infectious Disease Research Base (No. 20dz2210500), National Natural Science Foundation of China (No. 82070004, No. 82072557, and No. 81871882), Ministry of Science and Technology of China (No. 2022YFC2010005), National Key Research and Development Program of China(NO. 2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No. 20172005) and Science and Technology Commission of Shanghai Municipality(No. 20XD1402300).Innovative research team of high-level local universities in Shanghai.