CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

Abstract

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of “eat me” signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Keywords

osimertinib / anti-CD47 antibody / combination strategy / ADCP / EGFR

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Acknowledgements

This work was supported by the Science and Technology Development Fund, Macau SAR (File no. 0129/2019/A3). We sincerely thank Professor Xiuping Chen from University of Macau for the helpful discussions.

Compliance with ethics guidelines

Wei-Bang Yu, Yu-Chi Chen, Can-Yu Huang, Zi-Han Ye, Wei Shi, Hong Zhu, Jia-Jie Shi, Jun Chen, and Jin-Jian Lu declare no conflict of interest. BALB/c nude mice were maintained under SPF conditions in the animal facility of the Faculty of Health Science, University of Macau. The design of the animal experiments was approved by the Animal Care and Use Committee of University of Macau.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0934-1 and is accessible for authorized users.

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