2. Academic Validation
  3. Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade

Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade

  • J Immunother Cancer. 2019 Jul 12;7(1):178. doi: 10.1186/s40425-019-0646-5.
Yong-Qiang Chen 1,  Peng-Cheng Li 1,  Ning Pan 1,  Rong Gao 1,  Zhi-Fa Wen 1,  Tian-Yu Zhang 1,  Fang Huang 1,  Fang-Yuan Wu 2,  Xi-Long Ou 3,  Jin-Ping Zhang 4,  Xue-Jun Zhu 1 5,  Hong-Ming Hu 1 6,  Kang Chen 7 5,  Yun-Lang Cai 8,  Li-Xin Wang 9
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
  • 2 Department of Obstetrics and Gynecology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
  • 3 Department of Gastroenterology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
  • 4 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China.
  • 5 Jiangsu Province Hospital of Traditional Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 6 Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, 97213, USA.
  • 7 Department of Obstetrics and Gynecology and Barbara Ann Karmanos Cancer Institute, Wayne State University, Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Detroit, MI, 48201, USA.
  • 8 Department of Obstetrics and Gynecology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China. ylseu63@163.com.
  • 9 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China. lxwang@seu.edu.cn.
PMID: 31300052 DOI: 10.1186/s40425-019-0646-5
Abstract

Background: CD4+ T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4+ T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4+ T cells in the tumor microenvironment.

Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of Cancer patients were incubated with CD4+ T cells to examine the function and mechanism of TRAPs in CD4+ T cell differentiation and function. TRAPs-elicited CD4+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model.

Results: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of Cancer patients and tumor cell lines stimulated CD4+ T cell production of IL-6 via a TLR2-MyD88-NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4+ T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4+ T cells inhibited CD4+ and CD8+ effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4+ T cells markedly retarded tumor growth. Furthermore, B cell or CD4+ T cell depletion impeded tumor growth by increasing effector T cell function.

Conclusions: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4+ T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.

Keywords

CD4+ T cell; Extracellular vesicles (EVs); Heat shock protein 90α (HSP90α); IL-6; Regulatory B cell; Tumor-released autophagosome (TRAP).

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