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  3. Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade

Combination of MAPK inhibition with photothermal therapy synergistically augments the anti-tumor efficacy of immune checkpoint blockade

  • J Control Release. 2021 Apr 10;332:194-209. doi: 10.1016/j.jconrel.2021.02.020.
Xiaowei Liu 1,  Yanlin Feng 2,  Jie Xu 3,  Ying Shi 4,  Jiqiao Yang 1,  Rongjie Zhang 1,  Jinen Song 1,  Xin Bai 1,  Xi Wu 1,  Yu Bao 1,  Ya Luo 1,  Huifang Li 5,  Li Chai 5,  Changyang Gong 6,  Yan Wang 7,  Bo Chen 8,  Jianping Hu 9,  Yan Fu 10,  Yongzhang Luo 10,  Haiyuan Zhang 11,  Hubing Shi 12
Affiliations

Affiliations

  • 1 Laboratory of Tumor Targeted and Immune Therapy, Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, Sichuan, China.
  • 2 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 130022 Changchun, China; University of Science and Technology of China, Hefei, Anhui 230026, China.
  • 3 Institutes of Biological Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China.
  • 4 School of Medicine, University of Electronic Science and Technology of China, 610054 Chengdu, Sichuan, China.
  • 5 Research Core Facility, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China.
  • 7 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142 Beijing, China.
  • 8 Conmed Biosciences Inc, 610200 Chengdu, Sichuan, China.
  • 9 College of Pharmacy and Biological Engineering, Chengdu University, 610106 Chengdu, Sichuan, China.
  • 10 The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Beijing Key Laboratory for Protein Therapeutics, Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
  • 11 Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 130022 Changchun, China; University of Science and Technology of China, Hefei, Anhui 230026, China. Electronic address: zhangh@ciac.ac.cn.
  • 12 Laboratory of Tumor Targeted and Immune Therapy, Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, Sichuan, China. Electronic address: shihb@scu.edu.cn.
PMID: 33631225 DOI: 10.1016/j.jconrel.2021.02.020
Abstract

The combination of MAPK-targeted therapy and immune checkpoint blockade is one of the most promising regimens for patients with advanced melanoma. However, the synergistic efficacy of the combo regimen is still controversial in clinical trials. Here, we report that MAPK inhibition induced T-cell suppression within tumor microenvironment is mediated by attenuation of HSP27/HSP70 and deficiency of neoantigen presentation. To address this problem, we designed a photothermal-responsive on-demand controlled drug release gold nano-system to carry BRaf Inhibitor. The nano-system can be specifically delivered into tumor cells rather than T-cells, and effectively transformed the optical energy into heat energy upon laser irradiation. Combination of photothermal and targeted therapy significantly promoted immunogenic cell death and T-cell infiltration. On top of this regimen, systematically administration of PD-1 antibody not only suppressed local-treated tumor but also inhibited abscopal tumor by enhancing generalized immune-related antitumor response. More importantly, the triple-combo regimen could efficiently convert immune "cold" tumors into "hot" ones. In conclusion, our research proves the advantage of photothermal-targeted-immune triple combinatorial regimen in treating tumors which are clinical unresectable multifocal and lack of T-cell infiltration.

Keywords

Gold nanosystem; Immune checkpoint blockade; MAPK-targeted therapy; Melanoma; Photothermal therapy.

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