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αVEGFR2-MICA fusion antibodies enhance immunotherapy effect and synergize with PD-1 blockade

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Abstract

Antiangiogenic therapy has shown significant clinical benefits in gastric cancer (GC) and non-small cell lung cancer (NSCLC). However, their effectiveness is limited by the immunosuppressive tumor microenvironment. The MHC class I chain-related molecules A and B (MICA/B) are expressed in many human cancers, enabling elimination of cancer cells by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. To improve antiangiogenic therapy and prolong its efficacy, we generated a bi-specific fusion protein (mAb04-MICA). This was comprised of an antibody targeting VEGFR2 fused to a MICA α1–α2 ectodomain. mAb04-MICA inhibited proliferation of GC and NSCLC cells through specific binding to VEGFR2 and had superior anti-tumor efficacy in both GC and NSCLC-bearing mouse models compared with ramucirumab. Further investigation revealed that the mAb04-MICA promoted NKG2D+ NK cell activation and induced the tumor-associated macrophage (TAM) polarization from M2 type to M1 type both in vitro and in vivo. The polarization of TAMs upon NKG2D and MICA mediated activation has not yet been reported. Moreover, given the up-regulation of PD-L1 in tumors during anti-angiogenesis therapy, anti-PD-1 antibody enhanced the anti-tumoral activity of mAb04-MICA through stimulating infiltration and activation of NKs and CD8+T cells in responding tumors. Our findings demonstrate that dual targeting of angiogenesis and NKG2D, or in combination with the PD-1/PD-L1 blockade, is a promising anti-tumor therapeutic strategy. This is accomplished through maintaining or reinstating tumor immunosurveillance during treatment, which expands the repertoire of anti-angiogenesis-based cancer immunotherapies.

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Funding

This work was supported by the National Natural Science Foundation (NSFC81973223), and the National College Students Innovation and Entrepreneurship Training Program (202210316062Y, China).

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Author notes

  1. Mingzhu Pan and Fei Wang have contributed equally to this work.

Authors and Affiliations

  1. Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China

    Mingzhu Pan, Fei Wang, Lidi Nan, Siyu Yang, Jinyao Qi, Jiajun Xie, Shuai Shao, Hongyi zou, Min Wang & Juan Zhang

  2. Department of Internal Medicine, Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Fumou Sun

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  1. Mingzhu Pan
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Contributions

All authors contributed to the study conception and design. MP and FW designed and performed the experiments, carried out statistical analysis, and wrote the manuscript. LN guided anti-tumor efficacy in LLC model. SY, JQ, and HZ performed antibody-dependent cellular cytotoxicity assay, MTT assay, and helped with anti-tumoral activity in NSCLC model. JX and SS performed immunohistochemistry, PubMed searches and edited the manuscript. JZ proposed the study design, conducted the study supervision, and revised the manuscript. FS performed analysis and interpretation of data, and revised the manuscript. MW reviewed and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Fumou Sun or Juan Zhang.

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Pan, M., Wang, F., Nan, L. et al. αVEGFR2-MICA fusion antibodies enhance immunotherapy effect and synergize with PD-1 blockade. Cancer Immunol Immunother 72, 969–984 (2023). https://doi.org/10.1007/s00262-022-03306-1

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