CTLA4 blockade promotes vessel normalization in breast tumors via the accumulation of eosinophils

• Published in: International journal of cancer 2020-03, Vol.146 (6), p.1730-1740
• Main Authors: Zheng, Xichen, Zhang, Naidong, Qian, Long, Wang, Xuexiang, Fan, Peng, Kuai, Jiajie, Lin, Siyang, Liu, Changpeng, Jiang, Wen, Qin, Songbing, Chen, Haifeng, Huang, Yuhui
• Format: Article
• Language: English
• Subjects: Accumulation; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antitumor activity; anti‐CTLA4 therapy; Biomarkers; Breast cancer; Cancer; Cell Line, Tumor; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytotoxicity; Depletion; eosinophils; Eosinophils - drug effects; Eosinophils - immunology; Eosinophils - metabolism; Female; Growth inhibition; Humans; Immune checkpoint; Immunity; Immunomodulation - drug effects; Immunophenotyping; Interferon; Leukocytes (eosinophilic); Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Medical research; Metastases; Neoplasms - drug therapy; Neoplasms - etiology; Neoplasms - metabolism; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Perfusion; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; tumor vessel normalization; Tumors; γ-Interferon
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32829

Immune checkpoint blockade (ICB) has shown long‐term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti‐cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) treatment‐induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti‐CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti‐CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti‐CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy. What's new? Immune checkpoint blockade (ICB) confers long‐term survival benefits, but only in a minority of cancer patients. Improved tumor blood vessel perfusion under ICB positively correlates with its therapeutic outcomes, but the underlying mechanisms remain unclear. Here, the authors found that anti‐CTLA4 therapy increased tumor‐associated eosinophils in breast tumor models, which correlated with tumor vessel normalization and therapeutic efficacy. In vivo depletion of eosinophils abrogated the effect of anti‐CTLA4 therapy on tumor vessels and compromised antitumor immune responses. The findings uncovered an unidentified role of eosinophils in anti‐CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.