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07-03-2023 | Metastasis | Research

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

Authors: Yun-Shan Lin, Shu-Fen Chiang, Chia-Yi Chen, Wei-Ze Hong, Tsung-Wei Chen, William Tzu-Liang Chen, Tao-Wei Ke, Pei-Chen Yang, Ji-An Liang, An‑Cheng Shiau, K. S. Clifford Chao, Kevin Chih-Yang Huang

Published in: Cancer Immunology, Immunotherapy | Issue 7/2023

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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Title: Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation
Authors: Yun-Shan Lin
Shu-Fen Chiang
Chia-Yi Chen
Wei-Ze Hong
Tsung-Wei Chen
William Tzu-Liang Chen
Tao-Wei Ke
Pei-Chen Yang
Ji-An Liang
An‑Cheng Shiau
K. S. Clifford Chao
Kevin Chih-Yang Huang
Publication date: 07-03-2023
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Cytostatic Therapy
Colorectal Cancer
Colorectal Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 7/2023
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-023-03416-4

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