Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity

Cell Rep. 2018 Aug 14;24(7):1790-1801. doi: 10.1016/j.celrep.2018.07.043.

Abstract

Immune dysfunction is a strong factor in the resistance of cancer to treatment. Blocking immune checkpoint pathways is a promising approach to improve anti-tumor immunity, but the clinical efficacies are still limited. We previously identified follistatin-like 1 (FSTL1) as a determinant of immune dysfunction mediated by mesenchymal stromal/stem cells (MSCs) and immunoregulatory cells. Here, we demonstrate that blocking FSTL1 but not immune checkpoint pathways significantly suppresses cancer progression and metastasis in several mouse tumor models with increased MSCs. Expression of DIP2A (the receptor of FSTL1) in tumor cells is critical for FSTL1-induced immunoresistance. FSTL1/DIP2A co-positivity in tumor tissues correlates with poor prognosis in NSCLC patients. Thus, breaking the FSTL1-DIP2A axis may be a useful strategy for successfully inducing anti-tumor immunity.

Keywords: FSTL1; aging; antibody; cancer metastasis; immune checkpoint; immune exhaustion; immunosuppression; lung cancer; mesenchymal stromal/stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics*
  • Carrier Proteins / immunology
  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Female
  • Follistatin-Related Proteins / antagonists & inhibitors
  • Follistatin-Related Proteins / genetics*
  • Follistatin-Related Proteins / immunology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunity, Innate*
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / mortality
  • Male
  • Mesenchymal Stem Cells / immunology
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / immunology
  • Prognosis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Survival Analysis
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • Carrier Proteins
  • DIP2A protein, human
  • Follistatin-Related Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • FSTL1 protein, human