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Tumor-infiltrating OX40+ lymphocytes is an independent positive prognostic factor for patients with pancreatic ductal adenocarcinoma

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Abstract

Purpose

OX40 signaling pathway occupies a vital place in anti-tumor immunity; however, the role of tumor-infiltrating OX40+ lymphocytes in pancreatic ductal adenocarcinoma (PDAC) remains to be identified.

Methods

A total of 325 sequential PDAC patients who received curative tumor resection between January 2014 and December 2016 were enrolled. Tissues of these patients were immunohistochemically assessed for tumor infiltration of CD4+ T cells, CD8+ cytotoxic T cells (CTLs), and OX40+ lymphocytes. The frequency of OX40+ tumor-infiltrating lymphocytes (TILs) was then analyzed to various clinicopathological features, densities of tumor infiltration of CD4+ T cells and CTLs, and survival analysis was conducted using Kaplan–Meier (KM) curves. The risk scores of associated markers were calculated by the Cox proportional-hazards model.

Results

Our results showed that higher OX40+ lymphocytes infiltration was significantly correlated with superior median overall survival (OS) (25.8 vs 13.4 months, P < 0.001). Additionally, using univariate and multivariate Cox proportional hazards analyses, this study revealed that together with tumor differentiation, tumor size, serum CA199 levels, serum CA125 levels, and the infiltration of intratumoral CD8+ T cells. The abundance of OX40+ lymphocytes within the tumor was continued to be an independent predictor for OS (P = 0.023, HR = 0.713, 95% CI: 0.532–0.954).

Conclusions

This study demonstrated that intratumoral infiltration by a high number of OX40+ lymphocytes is a novel biomarker for favorable prognosis in resected PDAC patients, which implies that OX40-agonist-based immunotherapy might be a potential target in PDAC patients.

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Abbreviations

PDAC:

Pancreatic ductal adenocarcinoma

SR:

Survival rate

TME:

Tumor microenvironment

ICIs:

Immune checkpoint inhibitors

CTLs:

Cytotoxic T cells

TILs:

Tumor-infiltrating lymphocytes

HCC:

Hepatocellular carcinoma

CA:

Carbohydrate antigen

AJCC:

American Joint Committee on Cancer

TNM:

Tumor-node-metastasis

FFPE:

Formalin-fixed paraffin-embedded

IHC:

Immunohistochemistry

OS:

Overall survival

KM:

Kaplan–Meier

HR:

Hazard ratio

CI:

Confidence interval

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Acknowledgements

The authors would like to thank and appreciate Professor Baiyong Shen and Professor Hao Chen from the Department of General Surgery and Pancreatic Disease Center at Ruijin Hospital (Shanghai Jiao Tong University School of Medicine) for their support throughout the study. The authors are also grateful to Dr. Haimin Xu, Department of Pathology at Ruijin Hospital (Shanghai Jiao Tong University School of Medicine), for her excellent technical assistance.

Funding

This study was supported by Shanghai Municipal Key Clinical Specialty (No. shslczdzk06002).

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Author notes

  1. Qiwei Zhang, Weiwei Rui, and Yongsheng Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Qiwei Zhang, Xiaoxia Guo, Yu Zhou, Zhiyuan Wu & Xiaoyi Ding

  2. Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Weiwei Rui, Fei Yuan & Chaofu Wang

  3. Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yongsheng Jiang

  4. Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Yong Chen

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  1. Qiwei Zhang
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Contributions

Conception and design of the study: XD, CW, and ZW; Obtained funding: XD. Acquisition of clinical data: QZ and Yongsheng Jiang. Collection of samples: QZ, YJ, XG, and YZ. Histologic analysis: WR and FY. Statistical analysis and interpretation of data: QZ, YJ, and YC. Drafting the manuscript: QZ, WR, and YJ. Manuscript reviewing and study supervision: XD, CW, and ZW. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhiyuan Wu, Chaofu Wang or Xiaoyi Ding.

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The authors have declared that they have no competing interests.

Ethical approval

This study was approved by the Ethics Committee of Ruijin Hospital.

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Informed consent was obtained from all patients.

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Zhang, Q., Rui, W., Jiang, Y. et al. Tumor-infiltrating OX40+ lymphocytes is an independent positive prognostic factor for patients with pancreatic ductal adenocarcinoma. Clin Transl Oncol 24, 2029–2038 (2022). https://doi.org/10.1007/s12094-022-02864-1

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  • DOI: https://doi.org/10.1007/s12094-022-02864-1

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