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

Peng, Haitao; Xiao-yue, WU; Liu, Shaopeng; He, Miao; Xie, Chao; Zhong, Ran; Li, Jun; Tang, Chenshuo; Li, Caichen; Xiong, Shan; Zheng, Hongbo; He, Jianxing; Xu, Lisha; Liang, Wenhua

doi:10.1002/ctm2.1155

Cited by 33 publications

(31 citation statements)

References 77 publications

(170 reference statements)

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“…By canonical cell markers, nine major cell clusters of tumor cells and tumor‐infiltrated immune cells were detected. The histochemistry score 23 indicated a greater abundance of PDL1+ cells in TME of high inflammation group (Figure 4C). The expression of PDL1 was then used for subclass division of tumor cells and immune cells.…”

Section: Resultsmentioning

confidence: 94%

“…Multiplex immunofluorescence analysis was performed using previously described methods 23,24 . The Opal 7‐Color Manual IHC Kit (PerkinElmer, NEL811001KT) was used to stain slides from formalin‐fixed paraffin‐embedded NSCLC tissues.…”

Section: Methodsmentioning

confidence: 99%

“…Multiplex immunofluorescence analysis was performed using previously described methods. 23,24 The Opal 7-Color Manual IHC Kit (PerkinElmer, NEL811001KT) was used to stain slides from formalinfixed paraffin-embedded NSCLC tissues. The primary antibodies were anti-CD4 (ab133616), anti-CD8 (ab237709), anti-CD68 (ab192847), anti-FOXP3 (ab20034), anti-PANCK (ab7753) and anti-PDL1 (ab237726).…”

Section: Analysis Of Tmementioning

confidence: 99%

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Systemic inflammation influences the prognosis of patients with radically resected non‐small cell lung cancer and correlates with the immunosuppressive microenvironment

Wang

Sun

et al. 2023

Intl Journal of Cancer

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The impact of host condition on prognosis of non-small cell lung cancer (NSCLC) and the interaction between host and NSCLC remain unclear. This study investigated the association between systemic inflammation and prognosis and characteristics of radically resected NSCLC. This study consisted of a cohort study and an exploratory study of institutional prospective databases. All participants underwent video-assisted thoracoscopic lobectomy as the primary treatment. Systemic inflammation was assessed before surgery using the advanced lung cancer inflammation index and the systemic inflammation response index. Next-generation sequencing and multiplex immunofluorescence analysis were conducted to delineate tumor characteristics. In the cohort study including 1507 participants, high inflammation was associated with poor disease-free survival and overall survival before and after propensity score matching and in multivariable analysis.Systemic inflammation showed good prognostic value for stage IA-IB NSCLC, and the prognostic value diminished with upstaging of NSCLC. In the exploratory study including 217 adenocarcinomas, tumor microenvironment of high inflammation group showed a greater abundance of PDL1+ tumor cells and immune cells, which were independent from driver gene mutations and clinicopathological characteristics. Spatial analysis demonstrated a higher frequency of immune-suppressed cellular neighborhood, increased avoidance between immune cells and PDL1-tumor cells and compromised immune killing and presentation in tumor microenvironment of high inflammation group. Systemic inflammation showed limited association with genomic mutations. Systemic inflammation may influence the prognosis of NSCLC at both the systematic level and the local immune response. The correlation between high inflammation and immunosuppressive microenvironment indicates a novel thread for anticancer treatment.

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Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Analysis Of Tmementioning

confidence: 99%

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Systemic inflammation influences the prognosis of patients with radically resected non‐small cell lung cancer and correlates with the immunosuppressive microenvironment

Wang

Sun

et al. 2023

Intl Journal of Cancer

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“…For example, Peng et al. have shown that N1‐like neutrophils could enhance the activation of T and B cells in NSCLC, while nearby M2‐like macrophages exhibited inhibitory effects 46 . Leader et al.…”

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing analysis reveals transcriptional heterogeneity of multiple primary lung cancer

Guo,

Zhou,

Bie

et al. 2023

Clinical & Translational Med

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IntroductionWith the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial.ObjectiveOur study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC.MethodsWe performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC.ResultsA total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples.ConclusionsOur study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.

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“…Several studies reported that a higher density of CD8+ T cells neighboring CD8- T cells or regulatory T cells was associated with better prognosis of patients with NSCLC, indicating the potential significance of the CD8+ T cells limited in certain spatial scale [ 10 , 11 ]. Additionally, Peng et al provided a novel insight to decode spatial information of immune cell, through variables based on the intercellular distance reflecting the level of interaction [ 12 ]. Therefore, a comprehensive decipherment of the spatial structure is necessary for intratumoral CD8+ T cells in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Functional status and spatial architecture of tumor-infiltrating CD8+ T cells are associated with lymph node metastases in non-small cell lung cancer

Yang,

Cai,

et al. 2023

J Transl Med

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Background Anti-PD-(L)1 immunotherapy has been recommended for non-small cell lung cancer (NSCLC) patients with lymph node metastases (LNM). However, the exact functional feature and spatial architecture of tumor-infiltrating CD8 + T cells remain unclear in these patients. Methods Tissue microarrays (TMAs) from 279 IA-IIIB NSCLC samples were stained by multiplex immunofluorescence (mIF) for 11 markers (CD8, CD103, PD-1, Tim3, GZMB, CD4, Foxp3, CD31, αSMA, Hif-1α, pan-CK). We evaluated the density of CD8 + T-cell functional subsets, the mean nearest neighbor distance (mNND) between CD8 + T cells and neighboring cells, and the cancer-cell proximity score (CCPS) in invasive margin (IM) as well as tumor center (TC) to investigate their relationships with LNM and prognosis. Results The densities of CD8 + T-cell functional subsets, including predysfunctional CD8 + T cells (Tpredys) and dysfunctional CD8 + T cells (Tdys), in IM predominated over those in TC (P < 0.001). Multivariate analysis identified that the densities of CD8 + Tpredys cells in TC and CD8 + Tdys cells in IM were significantly associated with LNM [OR = 0.51, 95%CI (0.29–0.88), P = 0.015; OR = 5.80, 95%CI (3.19–10.54), P < 0.001; respectively] and recurrence-free survival (RFS) [HR = 0.55, 95%CI (0.34–0.89), P = 0.014; HR = 2.49, 95%CI (1.60–4.13), P = 0.012; respectively], independent of clinicopathological factors. Additionally, shorter mNND between CD8 + T cells and their neighboring immunoregulatory cells indicated a stronger interplay network in the microenvironment of NSCLC patients with LNM and was associated with worse prognosis. Furthermore, analysis of CCPS suggested that cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) selectively hindered CD8 + T cells from contacting with cancer cells, and were associated with the dysfunction of CD8 + T cells. Conclusion Tumor-infiltrating CD8 + T cells were in a more dysfunctional status and in a more immunosuppressive microenvironment in patients with LNM compared with those without LNM.

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

Cited by 33 publications

References 77 publications

Systemic inflammation influences the prognosis of patients with radically resected non‐small cell lung cancer and correlates with the immunosuppressive microenvironment

Systemic inflammation influences the prognosis of patients with radically resected non‐small cell lung cancer and correlates with the immunosuppressive microenvironment

Single‐cell RNA sequencing analysis reveals transcriptional heterogeneity of multiple primary lung cancer

Functional status and spatial architecture of tumor-infiltrating CD8+ T cells are associated with lymph node metastases in non-small cell lung cancer

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