Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells

Nat Commun. 2022 Jan 11;13(1):231. doi: 10.1038/s41467-021-27936-8.


Therapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8+ T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butyrophilins / genetics*
  • Butyrophilins / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CTLA-4 Antigen
  • Female
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Immunotherapy
  • Interleukin-17 / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Escape / physiology*
  • Tumor Microenvironment


  • BTNL2 protein, human
  • BTNL2 protein, mouse
  • Butyrophilins
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Interleukin-17