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The role of spatial interplay patterns between PD-L1-positive tumor cell and T cell in recurrence of locally advanced non-small cell lung cancer

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Abstract

Purpose

To explore the relationship between the spatial interaction of programmed death-ligand 1(PD-L1)-positive tumor cell and T cell with specific functions and the recurrence of non-small cell lung cancer (NSCLC) and optimize prognostic stratification.

Materials and methods

This study retrospectively included 104 patients with locally advanced NSCLC who underwent radical surgery. Tissue microarrays were constructed including tumor center (TC) and invasion margin (IM), and CK/CD4/CD8/PD-L1/programmed death-1 (PD-1) was labeled using multiplex immunofluorescence to decipher the counts and spatial distribution of tumor cells and T cells. The immune microenvironment and recurrence stratification were characterized using the Mann–Whitney U test and Cox proportional hazards model.

Result

Compared with the IM, the proportion of tumor cells (especially PD-L1+) was increased in the TC, while T cells (especially PD-1+) were decreased. An increase in TC PD-1+ CD8 T cells promoted relapse (HR = 2.183), while PD-L1+ tumor cells alone or in combination with T cells had no predictive value for relapse. In addition, in both TC and IM, CD8 were on average closer to PD-L1+ tumor cells than CD4, especially exhausted CD8. The effective density and percentage of PD-1+ CD4 T cells interacting with PD-L1+ tumor cells in the IM were both associated with recurrence, and the HRs increased sequentially (HRs were 2.809 and 4.063, respectively). Patients with low PD-1+CD4 count combined high PD-1+CD4 effective density showed significantly poorer RFS compared to those with high PD-1+CD4 count combined low PD-1+CD4 effective density, in both the TC and IM regions (HRs were 5.810 and 8.709, respectively).

Conclusion

Assessing the relative spatial proximity of PD-1/PD-L1 contributes to a deeper understanding of tumor immune escape and generates prognostic information in locally advanced NSCLC patients.

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Data Availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Abbreviations

DAPI:

4′,6-Diamidino-2-phenylindole

EGFR:

Epidermal growth factor receptor

FFPE:

Formalin-fixed, paraffin-embedded

IM:

Invasion margin

ICIs:

Immune checkpoint inhibitors

mIF:

Multiplex immunofluorescence

NSCLC:

Non-small cell lung cancer

NND:

Nearest neighbor distances

PD-L1:

Programmed death-ligand 1

PD-1:

Programmed death-1

RFS:

Relapse-free survival

TME:

Tumor microenvironment

TMA:

Tissue microarray

TC:

Tumor center

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82172866), the Shandong Provincial Natural Science Foundation (Grant No. ZR2021LZL005), the Shandong Provincial Natural Science Foundation (Grant No. ZR2019LZL019), and the Department of Science & Technology of Shandong Province (Grant No. 2021CXGC011102).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Liying Yang, Wei Zhang & Ligang Xing

  2. Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China

    Jujie Sun

  3. Shandong University Cancer Center, Shandong University, Jinan, China

    Guanqun Yang, Siqi Cai & Ligang Xing

  4. Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Fenghao Sun & Xiaorong Sun

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  1. Liying Yang
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  8. Xiaorong Sun
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Contributions

LY, LX, and XS contributed to conception and design of the study. LY, WZ, JS, GY, SC, and FS organized the database. LY, WZ, JS, GY, and SC performed the statistical analysis. LY wrote the first draft of the manuscript. LX and XS wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Corresponding author

Correspondence to Xiaorong Sun.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the Ethics Review Committee of Shandong Cancer Hospital and complied with the provisions of the Declaration of Helsinki. This study was a retrospective analysis, and informed consent was not required.

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Yang, L., Zhang, W., Sun, J. et al. The role of spatial interplay patterns between PD-L1-positive tumor cell and T cell in recurrence of locally advanced non-small cell lung cancer. Cancer Immunol Immunother 72, 2015–2027 (2023). https://doi.org/10.1007/s00262-023-03380-z

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