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

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

doi:10.1186/s12967-023-04154-y

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

J Transl Med. 2023 May 12;21(1):320. doi: 10.1186/s12967-023-04154-y.

Authors

Guanqun Yang^#^{1

2}, Siqi Cai^#^{1

2}, Mengyu Hu^{3

2}, Chaozhuo Li^{4

2}, Liying Yang⁵, Wei Zhang⁵, Jujie Sun⁶, Fenghao Sun⁷, Ligang Xing^{1

2}, Xiaorong Sun^{8

9}

Affiliations

¹ Shandong University Cancer Center, Shandong University, Jinan, Shandong, China.
² Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
³ Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
⁴ School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China.
⁵ Shandong Cancer Hospital and Institute and Shandong Academy of Medical Science, Jinan, Shandong, China.
⁶ Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.
⁷ Department of Nuclear Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, No.440, Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China.
⁸ Shandong University Cancer Center, Shandong University, Jinan, Shandong, China. xrsun@sdfmu.edu.cn.
⁹ Department of Nuclear Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, No.440, Jiyan Road, Huaiyin District, Jinan, 250117, Shandong, China. xrsun@sdfmu.edu.cn.

^# Contributed equally.

Abstract

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.

Keywords: CD8 + T cell; Dysfunction; Lung cancer; Multiplex immunofluorescence; Spatial architecture; Tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung* / pathology
Functional Status
Humans
Lung Neoplasms* / pathology
Lymphatic Metastasis / pathology
Lymphocytes, Tumor-Infiltrating / pathology
Prognosis
Tumor Microenvironment