Combination of DESI2 and IP10 gene therapy significantly improves therapeutic efficacy against murine carcinoma

// Chao Lin 1, * , HuaYing Yan 1, 2, * , Jun Yang 1 , Lei Li 1 , Mei Tang 1 , Xinyu Zhao 1 , Chunlai Nie 1 , Na Luo 3 , Yuquan Wei 1 and Zhu Yuan 1 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Chengdu, Sichuan University, Chengdu, 610041, China 2 Department of Functional Imaging, Sichuan Provincial Women’s and Children’s Hospital, Chengdu, 610031, China 3 Nankai University School of Medicine, Collaborative Innovation Center of Biotherapy, Tianjin, 300071, China * These authors contributed equally to this work Correspondence to: Zhu Yuan, email: yuanzhu@scu.edu.cn Keywords: DESI2, IP10, apoptosis, anti-angiogenesis, antitumor immunity Received: December 23, 2016 Accepted: April 20, 2017 Published: May 05, 2017 ABSTRACT DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo . The recombinant plasmid co-expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex. We found that, in vitro , the combination of DESI2 and IP10 more efficiently inhibited proliferation of CT26, LL2, SKOV3 and A549 cancer cells via apoptosis. In vivo , the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice. Mechanistically, the augmented antitumor activity in vivo was associated with induction of apoptosis and inhibition of angiogenesis. The anti-angiogenesis was further mimicked by inhibiting proliferation of immortalized HUVEC cells in vitro . Meanwhile, the infiltration of lymphocytes also contributed to the enhanced antitumor effects. Depletion of CD8+ T lymphocytes significantly abrogated the antitumor activity, whereas depletion of CD4+ T cells or NK cells showed partial abrogation. Our data suggest that the combined gene therapy of DESI2 and IP10 can significantly enhance the antitumor activity as apoptosis inducer, angiogenesis inhibitor and immune response initiator. The present study may provide a novel and effective method for treating cancer.