Journal Article

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

Cai, Siqi, Li, Chaozhuo, Sun, Jujie, Yang, Liying, Zhang, Wei, Xing, Ligang, Yang, Guanqun, Sun, Xiaorong, Hu, Mengyu, Sun, Fenghao

2023

Overview

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 (T predys ) and dysfunctional CD8 + T cells (T dys ), in IM predominated over those in TC ( P  < 0.001). Multivariate analysis identified that the densities of CD8 + T predys cells in TC and CD8 + T dys 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Antibodies / Antigens / Biomedical and Life Sciences / Biomedicine / Cancer microenvironment / Carcinoma, Non-Small-Cell Lung - pathology / Care and treatment / CD103 antigen / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes / CD8 + T cell / Cells / Diagnosis / Dysfunction / Fibroblasts / Fluorescent antibody technique / Foxp3 protein / Functional Status / Humans / Hypoxia-inducible factor 1a / Immunofluorescence / Immunoregulation / Immunotherapy / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - pathology / Lymph nodes / Lymphatic metastasis / Lymphatic Metastasis - pathology / Lymphatic system / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - pathology / Machine learning / Medical prognosis / Medicine/Public Health / Metastases / Metastasis / Microenvironments / Multiplex immunofluorescence / Multivariate analysis / Non-small cell lung carcinoma / Patient outcomes / Patients / PD-1 protein / Prevention / Prognosis / Risk factors / Small cell lung carcinoma / Spatial architecture / Tumor Microenvironment