Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer

Sha Zhao, Shengxiang Ren, Tao Jiang, Bo Zhu, Xuefei Li, Chao Zhao, Yijun Jia, Jinpeng Shi, Limin Zhang, Xiaozhen Liu, Meng Qiao, Xiaoxia Chen, Chunxia Su, Hui Yu, Caicun Zhou, Jun Zhang, D. Ross Camidge, Fred R. Hirsch

Research output: Contribution to journalArticlepeer-review

219 Scopus citations

Abstract

The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti–PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti–PD-1/ PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8þ T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFb amounts in both tumor and serum. Combining low-dose apatinib with anti–PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti–PD-1 in a small cohort of patients with pretreated advanced non–small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.

Original languageEnglish
Pages (from-to)630-643
Number of pages14
JournalCancer Immunology Research
Volume7
Issue number4
DOIs
StatePublished - Apr 2019

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