Using genetic and pharmacologic methods, Samanta et al. showed that exposing breast cancer cells to hypoxia prompted hypoxia-inducible factors to bind to and activate transcription of baculoviral IAP repeat-containing 2 (BIRC2), which codes for BIRC2 (also called cIAP1), an E3 ubiquitin-protein ligase that regulates NF-κB. BIRC2 knockdown increased CXCL9 mRNA and protein expression by breast cancer and melanoma cells and recruited activated CD8+ T and NK cells that inhibited tumor growth in mice. Blocking CXCL9 inhibited CD8+ T and NK cell migration to BIRC2-deficient tumors and enhanced sensitivity to anti-CTLA-4 and/or anti-PD-1.
Contributed by Paula Hochman
ABSTRACT: Immune checkpoint blockade (ICB) has led to therapeutic responses in some cancer patients for whom no effective treatment previously existed. ICB acts on T lymphocytes and other immune cells that are inactivated due to checkpoint signals that inhibit their infiltration and function within tumors. But for more than 80% of patients, immunotherapy has not been effective. Here, we demonstrate a cancer-cell-intrinsic mechanism of immune evasion and resistance to ICB mediated by baculoviral IAP repeat-containing 2 (BIRC2). Knockdown of BIRC2 expression in mouse melanoma or breast cancer cells increases expression of the chemokine CXCL9 and impairs tumor growth by increasing the number of intratumoral activated CD8+ T cells and natural killer cells. Administration of anti-CXCL9 neutralizing antibody inhibits the recruitment of CD8+ T cells and natural killer cells to BIRC2-deficient tumors. Most importantly, BIRC2 deficiency dramatically increases the sensitivity of mouse melanoma and breast tumors to anti-CTLA4 and/or anti-PD1 ICB.
Author Info: (1) Johns Hopkins Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns
Author Info: (1) Johns Hopkins Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Johns Hopkins Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) Johns Hopkins Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: gsemenza@jhmi.edu.
