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.