BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy
Open accessAbstract
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.
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In breast cancer and melanoma, HIF-dependent expression of BIRC2 led to decreased CXCL9 expression, which prevented the recruitment of CD8+ T cells and NK cells to the tumor.
“In breast cancer and melanoma, we demonstrated that HIF-dependent expression of BIRC2 led to decreased CXCL9 expression, which prevented the recruitment of CD8+ T cells and NK cells to the tumor (71).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [71]
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Salman, S., Meyers, D. J., Wicks, E. E., Lee, S. N., Datan, E., Thomas, A. M., Anders, N. M., Hwang, Y., Lyu, Y., Yang, Y., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci156774 · Cited by 111 · see citing works
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- Authors
- Samanta, D., Huang, T. Y.-T., Shah, R., Yang, Y., Pan, F., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 32
- Issue
- 8
- Pages
- 108073
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3080095331
- Cited by
- 49
- References
- 8
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 7 · 2023: 7 · 2022: 16 · 2021: 4
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Susan G. Komen
- American Cancer Society
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cIAP1, immune checkpoint blockade, cancer immunotherapy resistance, CXCL9, CD8+ T cells, natural killer cells, tumor immune evasion, melanoma, breast cancer, anti-CTLA-4, anti-PD-1, chemokine recruitment
- MeSH terms
- Animals, Humans, Immunity, Innate, Immunotherapy, Ubiquitin-Protein Ligases, Inhibitor of Apoptosis Proteins, Mice, Tumor Microenvironment
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