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Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation

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Abstract

The CD39-CD73–adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I–IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084–1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103–1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.

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Acknowledgements

We are grateful for the tissue microarray support from the Translation Research Core, China Medical University Hospital. This study was supported in part by China Medical University Hospital (DMR-CELL-2103, DMR-CELL-2102 and DMR-110-045, Taiwan), the Ministry of Science and Technology (MOST110-2628-B-039-005 and MOST110-2314-B-039-032, Taiwan), and the Health and welfare surcharge on tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW110-TDU-B-212-144024, Taiwan). This study was partially based on clinical information from the China Medical University Hospital Cancer Registry. Experiments and data analysis were performed in part through the use of the Medical Research Core Facilities Center, Office of Research & Development at China medical University, Taichung, Taiwan, R.O.C.

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Author notes

  1. K. S. Clifford Chao and Kevin Chih-Yang Huang these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC

    Yun-Shan Lin

  2. Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, 42055, Taiwan, ROC

    Shu-Fen Chiang

  3. Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC

    Chia-Yi Chen, Wei-Ze Hong, Pei-Chen Yang, An‑Cheng Shiau & K. S. Clifford Chao

  4. Graduate Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan, ROC

    Tsung-Wei Chen & K. S. Clifford Chao

  5. Department of Pathology, Asia University Hospital, Asia University, Taichung, 41354, Taiwan, ROC

    Tsung-Wei Chen

  6. Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan, ROC

    William Tzu-Liang Chen

  7. Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC

    William Tzu-Liang Chen & Tao-Wei Ke

  8. Department of Surgery, School of Medicine, China Medical University, Taichung, 40402, Taiwan, ROC

    William Tzu-Liang Chen

  9. School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC

    Tao-Wei Ke

  10. Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan, ROC

    Ji-An Liang & K. S. Clifford Chao

  11. Department of Radiotherapy, School of Medicine, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC

    Ji-An Liang & K. S. Clifford Chao

  12. Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan, ROC

    An‑Cheng Shiau & Kevin Chih-Yang Huang

  13. Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan, ROC

    Kevin Chih-Yang Huang

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Contributions

Data curation, YL and TC; Formal analysis, SC, WTC, KCH, JL and AS; Funding acquisition, KSCC and KCH; Investigation, WTC, TK and PY; Animal experiments and flow cytometry analysis, KCH, CC and WH; Project administration, KCH; Resources, WTC, TK and KSCC; Supervision, KSCC; Writing—original draft, KCH; Writing—review & editing, KSCC.

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Correspondence to K. S. Clifford Chao or Kevin Chih-Yang Huang.

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This study was reviewed and approved by the Internal Review Board (IRB) of China Medical University Hospital [Protocol number: CMUH105-REC2-073]. The method was carried out in accordance with the committee’s approved guidelines.

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Lin, YS., Chiang, SF., Chen, CY. et al. Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation. Cancer Immunol Immunother 72, 2283–2297 (2023). https://doi.org/10.1007/s00262-023-03416-4

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