Chemotherapy induces enrichment of CD47 + /CD73 + /PDL1 + immune evasive triple-negative breast cancer cells
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Significance Cytotoxic chemotherapy is frequently used in patients with triple-negative breast cancer (TNBC). Although patients initially respond to the treatment, the cancer often comes back and kills the patient. Recent studies have demonstrated that cancer cells express genes that protect them from killing by immune cells, but the stimulus that prompts this response is unknown. We show that when TNBC cells are treated with chemotherapy, the surviving cells turn on genes that enable them to escape killing by the immune system. We identify hypoxia-inducible factors (HIFs), which are known to promote metastasis of TNBC, as responsible for this countertherapeutic effect. We show that coadministration of an HIF inhibitor with chemotherapy blocks the ability of surviving TNBC cells to evade the immune system.
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Acriflavine treatment of tumor-bearing mice increases intratumoral CD8+ T cells and NK cells.
“Acriflavine treatment of tumor-bearing mice was recently reported to increase intratumoral CD8+ T cells and NK cells (42, 43).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [42]
In “Acriflavine Blocks Chemotherapy-Induced Immune Evasion in a Syngeneic Mouse Model” (page unavailable), acriflavine coadministration restored intratumoral CD8+ effector T cells reduced by chemotherapy. The paper does not report an increase in intratumoral NK cells with acriflavine; it says carboplatin had no effect on their percentage. The CD8+ finding is also specific to acriflavine given with chemotherapy, not acriflavine treatment alone. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn human breast cancer cells, HIF-dependent expression of CD47, CD73, and PDL1 inhibited the ability of both the innate and adaptive immune systems to kill cancer cells.
“We previously showed that in human breast cancer cells HIF-dependent expression of CD47, CD73, and PDL1 inhibited the ability of both the innate and adaptive immune systems to kill cancer cells (42).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [42]
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- Authors
- Samanta, D., Park, Y., Ni, X., Li, H., Zahnow, C. A., Gabrielson, E., Pan, F., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-01-24
- Volume
- 115
- Issue
- 6
- Pages
- E1239-E1248
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5819443
- OpenAlex
- W2785041354
- Cited by
- 302
- References
- 63
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 35 · 2023: 47 · 2022: 53 · 2021: 45 · 2020: 43 · 2019: 28 · 2018: 17 · 2015: 1
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Emerson Collective Cancer Research Fund (n/a)
- American Cancer Society (RP-16-239-06-COUN)
- Cindy Rosencrans Fund for Triple Negative Breast Cancer (n/a)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- triple-negative breast cancer, chemoresistance, immune evasion, CD47, CD73, PD-L1, hypoxia-inducible factor, HIF inhibitors, tumor immune evasion, tumor cell survival
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Tumor Cells, Cultured, 5'-Nucleotidase, Gene Expression Regulation, Neoplastic, Apoptosis, Tumor Escape, Xenograft Model Antitumor Assays, Mice, Hypoxia-Inducible Factor 1, CD47 Antigen, GPI-Linked Proteins, B7-H1 Antigen, Triple Negative Breast Neoplasms
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