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Photodynamic therapy improves the outcome of immune checkpoint inhibitors via remodelling anti-tumour immunity in patients with gastric cancer

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Abstract

Background

Photodynamic therapy (PDT) plays an immunoregulatory role in tumours. Here, we conducted a retrospective patient analysis to evaluate the effectiveness of PDT plus immune checkpoint inhibitors (ICIs) in gastric cancer. Further, we performed a dynamic analysis of gastric cancer patients receiving PDT to clarify its effects on anti-tumour immunity.

Methods

Forty ICI-treated patients that received PDT or not were retrospectively analysed. Five patients with gastric adenocarcinoma were enrolled for sample collection before and after PDT. Single-cell RNA/T cell receptor (TCR) sequencing, flow cytometry and histological exanimation were used to analyse the collected specimens.

Results

Patients in PDT group had a significantly better OS after ICI treatment than those in No PDT group. Single-cell analysis identified ten cell types in gastric cancer tissues and four sub-populations of T cells. Immune cell infiltration increased in the tumours after PDT and the circular immune cells showed consistent alterations. TCR analysis revealed a specific clonal expansion after PDT in cytotoxic T lymphocytes (CTL), but a constriction in Tregs. The B2M gene is upregulated in tumour cells after PDT and is associated with immune cell infiltration. Several pathways involving the positive regulation of immunity were enriched in tumour cells in the post-PDT group. The interactions following PDT were increased between tumour cells and effector cells but decreased between Tregs and other immune cells. Some co-stimulatory signaling emerged, whereas co-inhibitory signaling disappeared in intercellular communication after PDT.

Conclusions

PDT elicits an anti-tumour response through various mechanisms and is promising as an adjuvant to enhance ICI benefit.

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Availability of data and materials

All data supporting this study have been presented in the full text or online supplementary files. Other relevant materials can be obtained on reasonable request to the corresponding author.

Abbreviations

ICIs:

Immune checkpoint inhibitors

PDT:

Photodynamic therapy

ICD:

Immunogenic cell death

scRNA/TCR-seq:

Single-cell RNA/T cell receptor (TCR) sequencing

OS:

Overall survival

HE:

Hematoxylin–eosin

PBS:

Phosphate buffered saline

UMIs:

Unique molecule identifiers

PCA:

Principal component analysis

t-SNE:

T-distributed stochastic neighbour embedding

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

TCGA:

The cancer genome atlas

NKT:

Natural killer T cells

Th:

T helper cells

Treg:

CD4+ regulatory T cells

CTL:

CD8+ cytotoxic T cells

HRs:

Hazard ratios

CIs:

Confidence intervals

HSC:

Haematopoietic stem cells

TSAs:

Tumour specific antigens

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Acknowledgements

The authors would like to thank BMKCloud (http://www.biocloud.net/) for providing supports in data process, management and figure drawing. We thank Chen Yu, Tianliang Lu, and Rui Zhang for their advice in bioinformatics analysis and Xiaohong Liu for her assistance in sample collection. We also thank the patients and their families who donated the tissue and blood samples in this study.

Funding

This work was supported by the Key Project of Science and Technology in Gansu province (22ZD6FA054 and 19ZD2WA001), Key Talents Project of Gansu Province (2019RCXM020), Science and Technology Project of Chengguan District of Lanzhou City (2020SHFZ0039 and 2020JSCX0073), and Medical Innovation and Development Project of Lanzhou University (lzuyxcx-2022-160, lzuyxcx-2022-45, and lzuyxcx-2022-88).

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Author notes

  1. Yang Yu and Bo Xu contributed equally to this work.

Authors and Affiliations

  1. The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, China

    Yang Yu, Bo Xu, Lin Xiang, Tianlong Ding, Na Wang, Rong Yu, Baohong Gu, Lei Gao, Ewetse Paul Maswikiti, Yunpeng Wang, Haiyuan Li, Yuping Bai, Peng Zheng, Chenhui Ma, Bofang Wang, Xueyan Wang & Hao Chen

  2. The Second Clinical Medical College, Lanzhou University, Lanzhou, China

    Yang Yu, Bo Xu, Lin Xiang, Tianlong Ding, Na Wang, Rong Yu, Baohong Gu, Lei Gao, Ewetse Paul Maswikiti, Yunpeng Wang, Haiyuan Li, Yuping Bai, Peng Zheng, Chenhui Ma, Bofang Wang & Xueyan Wang

  3. Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China

    Tao Zhang

  4. Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China

    Hao Chen

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  1. Yang Yu
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Contributions

YY and HC: had the idea of this study. YY and HC: conceived and designed the study. YY: performed most of the experiments, including single-cell sequencing, flow cytometry, and data analysis. BX, LX, NW, RY, and LG: contributed to the recruitment and management of patients. TLD, EPM, BX, and YPW: performed sample collection. HYL and BHG: helped with the processing and preparation of single-cell suspensions. CHM, BFW, and XYW: collected patient information and made the follow-up. YY and TZ: generated the statistical strategy. YY: visualised and interpreted the results and drafted the manuscript. YPB, LX, PZ and HC: provided clinical perspectives for the interpretation of results. HC and LX: reviewed and revised the manuscript. HC obtained funding to support all aspects of this study. YY and HC: have read and verified the underlying data. All authors read and approved the final version of the manuscript for submission.

Corresponding author

Correspondence to Hao Chen.

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The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

This study was approved by the Institutional Research Ethics Committee of the Lanzhou University Second Hospital (2021A-146). Informed consent was obtained from all included patients.

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Yu, Y., Xu, B., Xiang, L. et al. Photodynamic therapy improves the outcome of immune checkpoint inhibitors via remodelling anti-tumour immunity in patients with gastric cancer. Gastric Cancer 26, 798–813 (2023). https://doi.org/10.1007/s10120-023-01409-x

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