Lexi Goehring

Background:  Breast Cancer is the second most common cancer affecting women globally. While breast cancer generally has a high survival rate, Triple Negative Breast Cancer is a subtype that has a 50% recurrence rate in the first three to five years after diagnosis, and metastatic TNBC has a median survival time of 10.2 months; This is likely due to its lack of responsiveness to standard therapies because this particular subtype lacks many of the therapeutic targets- estrogen, progesterone, and human epidermal growth factor 2 receptors. Many of these tumors are unresponsive to other chemotherapy agents that do not bind these receptors in addition to immune blockade therapies despite the high immunogenicity of TNBC. While the resistance mechanism is unknown, hypoxia may propagate the immunosuppressive TME contributing to this resistance.

Objective: In this review, we explored the effects of hypoxia on TNBC resistance to the chemotherapy agent docetaxel (DTX) and anti-PD-1 immune blockade therapy.

Search Methods:  A literature search was conducted through PubMed using the following terms “triple negative breast cancer” “hypoxia” “resistance” “anti-PD-1” “immunosuppressive TME” “epidemiology” within the timeframe from 2017-2023.

Results:  Studies indicated that there was a decrease in cell lysis of hypoxic TNBC cell lines MB-231 and MB-468 when treated with the chemotherapy agent DTX when compared to cell lines under normoxic conditions. MiRNA expression of the hypoxic TNBC cells showed reduced expression of the microRNA miR-494. Upon treating the hypoxic tumor cells with hypoxia inducible factor (HIF) inhibitors and DTX, there was an increase in miR-494 and cell lysis.  Mouse models with 4T07 tumor cells expressing green fluorescent protein (GFP) were injected with anti-PD-1 T cells. IF analysis showed the surviving GFP expressing tumor cells formed a cluster and sequencing indicated upregulation of HIF1 alpha. Flow cytometry showed lower CD8 T cell infiltration, exhausted CD8 T cells with diminished effector functions and reduced IFN-gamma expression. Studies investigating resistance to immune blockade therapy used transfected two TNBC cell lines BT549 and MDA-MB-231 with lentivirus that contained the pLenti-V5-luc plasmid so the cells expressed luciferase and treated them with hypoxic T and natural killer cells as well as the anti-PD-1 antibody. In comparison with the normoxic immune cells, there was decreased cell lysis. Upon treatment of HIF and other hypoxia related gene and enzyme inhibitors as well as anti-PD-1, cell lysis increased and in some cases was restored to the level seen under normal conditions.

Conclusions:  Hypoxia leads to the upregulation of HIFs and the downregulation of miR-494 which decreases the efficacy of TNBC to DTX and anti-PD-1 therapy. Hypoxia-induced pathways facilitate the formation of an immunosuppressive TME with decreased CD8 T cell infiltration, reduced IFNY expression and increased T cell exhaustion. HIF inhibitors and miR-494 mimics may increase the efficacy of standard therapies.

Work Cited:

1. Li H, Sun X, Li J, et al. Hypoxia induces docetaxel resistance in triple-negative breast cancer via the HIF-1α/miR-494/Survivin signaling pathway. Neoplasia. 2022;32:100821. doi:10.1016/j.neo.2022.100821
2. Baldominos P, Barbera-Mourelle A, Barreiro O, et al. Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell. 2022;185(10):1694-1708.e19. doi:10.1016/j.cell.2022.03.033
3. Ma S, Zhao Y, Lee WC, et al. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat Commun. 2022;13(1):4118. Published 2022 Jul 15. doi:10.1038/s41467-022-31764-9
4. Won, K., & Won, K. (2020). Triple‑negative breast cancer therapy: Current and future perspectives (Review). International Journal of Oncology, 57, 1245-1261. https://doi.org/10.3892/ijo.2020.5135
5. Li, Y., Zhang, H., Merkher, Y., Chen, L., Liu, N., Leonov, S., & Chen, Y. (2022). Recent advances in therapeutic strategies for triple-negative breast cancer. Journal of hematology & oncology, 15(1), 121. https://doi-org.srv-proxy1.library.tamu.edu/10.1186/s13045-022-01341-0
6. Borri, F., & Granaglia, A. (2021). Pathology of triple negative breast cancer. Seminars in Cancer Biology, 72, 136–145. https://doi.org/10.1016/j.semcancer.2020.06.005
7. Sporikova, Z., Koudelakova, V., Trojanec, R., & Hajduch, M. (2018). Genetic markers in triple-negative breast cancer. Clinical Breast Cancer, 18(5). https://doi.org/10.1016/j.clbc.2018.07.023
8. Jafari, S. H., Saadatpour, Z., Salmaninejad, A., Momeni, F., Mokhtari, M., Nahand, J. S., Rahmati, M., Mirzaei, H., & Kianmehr, M. (2018). Breast cancer diagnosis: Imaging techniques and biochemical markers. Journal of Cellular Physiology, 233(7), 5200–5213. https://doi.org/10.1002/jcp.26379
9. Chen, X., Feng, L., Huang, Y., Wu, Y., & Xie, N. (2022). Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer. Cancers, 15(1), 104. https://doi.org/10.3390/cancers15010104