BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy

Debangshu Samanta; Tina Yi-Ting Huang; Rima Shah; Yongkang Yang; Fan Pan; Gregg L Semenza

doi:10.1016/j.celrep.2020.108073

BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy

Cell Rep. 2020 Aug 25;32(8):108073. doi: 10.1016/j.celrep.2020.108073.

Authors

Debangshu Samanta¹, Tina Yi-Ting Huang², Rima Shah², Yongkang Yang¹, Fan Pan³, Gregg L Semenza⁴

Affiliations

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.

PMID: 32846130
DOI: 10.1016/j.celrep.2020.108073

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.

Keywords: NF-κB; anti-tumor immunity; cancer immunosuppression; hypoxia-inducible factors; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Immunity, Innate / immunology*
Immunotherapy / methods*
Inhibitor of Apoptosis Proteins / metabolism*
Mice
Tumor Microenvironment
Ubiquitin-Protein Ligases / metabolism*

Substances

Inhibitor of Apoptosis Proteins
BIRC2 protein, human
Ubiquitin-Protein Ligases