2. Academic Validation
  3. Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer

Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer

  • EMBO Mol Med. 2022 Jan 11;14(1):e14502. doi: 10.15252/emmm.202114502.
Qian Zhou 1,  Jinxia Liang 1,  Tong Yang 1,  Jin Liu 1,  Bo Li 1 2,  Yingchang Li 1,  Zhenzhen Fan 1,  Weida Wang 3,  Wensheng Chen 1 4,  Sujing Yuan 3,  Meng Xu 4,  Qigui Xu 5,  Zhidong Luan 5,  Zhongjun Xia 3,  Penghui Zhou 3,  Yadong Huang 6,  Liang Chen 4 6
Affiliations

Affiliations

  • 1 Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
  • 2 MOE Key Laboratory of Glucolipid Metabolic Diseases, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, College of Chinese Medicine Research, Guangdong Pharmaceutical University, Guangzhou, China.
  • 3 State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Oncology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 5 Translational medicine laboratory, People's Hospital of Yangjiang City, Guangdong, China.
  • 6 Guangdong Province Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.
PMID: 34898004 DOI: 10.15252/emmm.202114502
Abstract

Impressive clinical benefit is seen in clinic with PD-1 inhibitors on portion of Cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor-associated macrophage (TAM), a type of M2-polarized macrophage, eliminates or suppresses T-cell-mediated anti-tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti-tumor therapy. Here, we conducted a high-throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF-κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1-like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD-1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD-1 inhibitors for patients with solid tumors.

Keywords

M1 macrophage; M2 macrophage; immunotherapy; tumor microenvironment; tumor-associated macrophage.

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