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Article

Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer

1
Department of Microbiology, Immunology & Molecular Genetics, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA
2
Department of Urology, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA
3
Mays Cancer Center, San Antonio, TX 78229, USA
4
Long School of Medicine, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA
5
Department of Pharmacology, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(22), 3875; https://doi.org/10.3390/cancers16223875
Submission received: 6 October 2024 / Revised: 16 November 2024 / Accepted: 17 November 2024 / Published: 19 November 2024

Simple Summary

Although bladder cancer (BCa) is known for its immunogenic characteristics, it often shows limited responsiveness to currently approved immunotherapies. Our previous research identified natural killer (NK) cells as significant contributors to improved survival outcomes in BCa patients. In this study, we found that eribulin, a microtubule destabilizer typically used for breast cancer, can activate NK cells. While clinical trials are exploring the use of eribulin in BCa treatment, the underlying mechanism was previously unknown. We demonstrated that low-dose eribulin activates NK cells, leading to reduced tumor burden and improved survival in various murine models. Mechanistically, eribulin enhanced NK cell migration and cytotoxicity against BCa cells, promoted an anti-tumor NK cell phenotype, and reduced exhaustion markers, uncovering an unexpected role of low-dose chemotherapy in boosting NK cell-mediated anti-tumor immunity. Given eribulin’s clinical availability, our findings support its potential as a rapid bench-to-bedside immune-adjuvant treatment for BCa.

Abstract

Despite its immunogenic nature, bladder cancer (BCa) responds sub-optimally to FDA-approved immunotherapy. Background/Objectives: We have previously shown that natural killer (NK) cells are major contributors to overall patient survival in BCa. In our efforts to identify clinically approved agents that enhance NK cell activation, we identified eribulin, a microtubule destabilizer primarily used in breast cancer. Ongoing clinical trials are investigating the potential integration of eribulin into the standard of care in BCa; however, the mechanistic rationale for these trials remains unclear. Methods: Here, we explore the effects of low-dose eribulin on direct NK cell activation in vitro, including on primary patient samples, and in vivo utilizing multiple murine models. Flow cytometry and RNA sequencing were employed to identify the mechanism of NK cell activation by eribulin, which was associated with increased migration and cytotoxicity of NK cells against BCa cells. Results: We found that localized eribulin instillation significantly reduces bladder tumor burden and improves survival in primary BCa in an NK cell-dependent manner. Importantly, eribulin promoted the shift of patient-derived intratumoral NK cells towards an anti-tumor CD49a+ CD103+ NK subset (ieILC1-like) while diminishing the dysfunctional NR4A2-expressing CD49a NK subset. Moreover, it decreased the overall expression of exhaustion markers on NK cells, a pattern replicated in our murine models. Conclusion: These findings are paradigm-shifting given that chemotherapy is traditionally considered immunosuppressive. Our study reveals the novel effect of low-dose eribulin chemotherapy in inhibiting bladder tumor growth by enhancing anti-tumor NK cell immunity, challenging previous assumptions and opening new therapeutic approaches to improve antitumor immunity.
Keywords: bladder cancer; NK cells; immunotherapy; innate lymphoid cells bladder cancer; NK cells; immunotherapy; innate lymphoid cells

Share and Cite

MDPI and ACS Style

Hassouneh, Z.; Noel, O.D.V.; Ji, N.; Kim, M.E.; Svatek, J.; Svatek, R.S.; Risinger, A.L.; Mukherjee, N. Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer. Cancers 2024, 16, 3875. https://doi.org/10.3390/cancers16223875

AMA Style

Hassouneh Z, Noel ODV, Ji N, Kim ME, Svatek J, Svatek RS, Risinger AL, Mukherjee N. Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer. Cancers. 2024; 16(22):3875. https://doi.org/10.3390/cancers16223875

Chicago/Turabian Style

Hassouneh, Zaineb, Onika D. V. Noel, Niannian Ji, Michelle E. Kim, Jordan Svatek, Robert S. Svatek, April L. Risinger, and Neelam Mukherjee. 2024. "Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer" Cancers 16, no. 22: 3875. https://doi.org/10.3390/cancers16223875

APA Style

Hassouneh, Z., Noel, O. D. V., Ji, N., Kim, M. E., Svatek, J., Svatek, R. S., Risinger, A. L., & Mukherjee, N. (2024). Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer. Cancers, 16(22), 3875. https://doi.org/10.3390/cancers16223875

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