The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing

Abstract

A thorough interrogation of the immune landscape is crucial for immunotherapy strategy selection and prediction of clinical responses in non-small-cell lung cancer (NSCLC) patients. Single-cell RNA sequencing (scRNA-seq) techniques have prompted the opportunity to dissect the distinct immune signatures between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of NSCLC. Here, we performed scRNA-seq on 72,475 immune cells from 40 samples of tumor and matched adjacent normal tissues spanning 19 NSCLC patients, and drew a systematic immune cell transcriptome atlas. Joint analyses of the distinct cellular compositions, differentially expressed genes (DEGs), cell–cell interactions, pseudotime trajectory, transcriptomic factors and prognostic factors based on The Cancer Genome Atlas (TCGA), revealed the central roles of cytotoxic and effector T and NK cells and the distinct functional macrophages (Mφ) subtypes in the immune microenvironment heterogeneity between LUAD and LUSC. The dominant subtype of Mφ was FABP4-Mφ in LUAD and SPP1-Mφ in LUSC. Importantly, we identified a novel lymphocyte-related Mφ cluster, which we named SELENOP-Mφ, and further established its antitumor role in both types, especially in LUAD. Our comprehensive depiction of the immune heterogeneity and definition of Mφ clusters could help design personalized treatment for lung cancer patients in clinical practice.

Multiplex immunofluorescence and single‐cell transcriptomic profiling reveal the spatial cell interaction networks in the non‐small cell lung cancer microenvironment

“…In conclusion, T cells, CSCs and macrophages were crucial contributors to the heterogeneity in TME between LUAD and LUSC, aligning with the recent findings by Wang et al. 41 …”

“…Closer proximity and stronger interaction between CD8+ T cells were observed in LUAD, whereas LUSC featured spatial proximity among PD‐L1+ cells, CD133+ CSCs and macrophages. In conclusion, T cells, CSCs and macrophages were crucial contributors to the heterogeneity in TME between LUAD and LUSC, aligning with the recent findings by Wang et al 41 …”

Identification and integration analysis of a novel prognostic signature associated with cuproptosis-related ferroptosis genes and relevant lncRNA regulatory axis in lung adenocarcinoma

“…The prognostic signature established with TCGA-LUAD data, validated by external datasets in the GEO database, and the comparison of nomogram and DCA can indicate that our prognostic signature related to CRFGs has better results and greater advantages in predicting the prognosis of LUAD patients, which has some significance for clinical application. The TME occupies an important position in tumorrelated research, and the evaluation of the immune system facilitates the development of personalized immunotherapy strategies for LUAD patients [44]. It has been suggested that the ferroptosis score and cuproptosis-related gene score are important for TME cell infiltration in LUAD patients and assist in assessing the effects of immunotherapy [18,45].…”

“…The TME occupies an important position in tumor-related research, and the evaluation of the immune system facilitates the development of personalized immunotherapy strategies for LUAD patients [ 44 ]. It has been suggested that the ferroptosis score and cuproptosis-related gene score are important for TME cell infiltration in LUAD patients and assist in assessing the effects of immunotherapy [ 18 , 45 ].…”

Sex-biased molecular differences in lung adenocarcinoma are ethnic and smoking specific

“…SCGB3A2 is predominantly expressed in the lung airway epithelial cells [ 39 , 40 ]. Previous study has demonstrated that LUAD cells with highly expressed SCGB3A2 exhibited anti-inflammatory features [ 41 ], it was not clarified whether this was related to the enhanced efficacy of immunotherapy. Furthermore, SCGB3A2 is identified as a downstream target for the homeodomain transcription factor NK2 Homeobox 1 ( NKX2-1 ) (also known as TTF1 ) [ 42 ], which is utilized as a marker for LUAD diagnosis [ 43 ].…”