BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy

Debangshu Samanta, Tina Yi Ting Huang, Rima Shah, Yongkang Yang, Fan Pan, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number108073
JournalCell Reports
Volume32
Issue number8
DOIs
StatePublished - Aug 25 2020

Keywords

  • NF-κB
  • anti-tumor immunity
  • cancer immunosuppression
  • hypoxia-inducible factors
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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