Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment

Theranostics. 2021 May 12;11(14):7029-7044. doi: 10.7150/thno.60040. eCollection 2021.


Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.

Keywords: IL-6; PD-1; Rab37; transcription; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / metabolism
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism*
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron
  • Prognosis
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*
  • rab GTP-Binding Proteins / ultrastructure


  • CTLA-4 Antigen
  • Interleukin-6
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Rab37 protein, mouse
  • rab GTP-Binding Proteins