Radium-223 dichloride causes transient changes in natural killer cell population and cytotoxic function

Abstract

Rationale

Natural killer (NK) cells play an important role in both the innate and adaptive arms of the immune system. While previous studies have demonstrated the effects of ionizing radiation on cytotoxic function of NK cells, little is known about how a chronic exposure to high LET alpha particles emitted by radionuclides will affect both NK population size and function. This study was conducted to determine the effects of ²²³RaCl₂ on splenic NK cell population size and function in Swiss Webster mice.

Methods

Swiss Webster mice were administered intravenously with 0, 50, or 600 kBq/kg ²²³RaCl₂. Spleens were harvested at 5, 12, and 19 days post-administration. The numbers of splenocytes per spleen were enumerated and flow cytometry was used to assess changes in the distribution of splenocyte subpopulations of B, CD4 and CD8 T lymphocytes, and NK cells. NK functional activity was quantified using YAC-1 target cells and the ⁵¹Cr-release assay.

Results

The total number of splenocytes was unaffected by ²²³RaCl₂. However, significant changes in the distribution of splenocyte subpopulations were observed for NK cells and CD8 T lymphocytes. NK functional activity was enhanced substantially relative to controls at 12 days post-administration, but decreased markedly by day 19.

Conclusion

NK functional activity is both diminished and enhanced by ²²³RaCl₂ depending on both administered activity and time post-administration. These results suggest that there may be an optimum window of time to combine the ²²³RaCl₂-induced antitumor NK cell response with other cancer therapies that elicit immune activation.

Keywords:

• natural killer cell
• radium-223
• alpha particle
• radiopharmaceutical therapy
• radiation induced immune response

Acknowledgments

The authors thank the NJMS Flow Cytometry Core for their tireless maintenance and troubleshooting assistance for matters pertaining to their instruments and the data generated thereof.

Disclosure statement

This study was supported in part by Grant 1R01CA198073 from the NIH, and New Jersey Commission on Cancer Research Pre-doctoral Fellowship Grant #DFHS15PPC009 (CNL). No other potential conflicts of interest relevant to this article exist.

Additional information

Funding

This study was supported in part by Grant 1R01CA198073 from the NIH, and New Jersey Commission on Cancer Research Pre-doctoral Fellowship Grant #DFHS15PPC009 (CNL). National Cancer Institute.

Notes on contributors

Calvin N. Leung

Calvin N. Leung is an MD PhD student at Rutgers New Jersey Medical School and Rutgers School of Graduate Studies, Newark, NJ, USA.

Donna M. Howell

Donna M. Howell, Ph.D., is Acting Dean and Chair of Natural Sciences at Middlesex College, Edison, NJ, USA, and Adjunct Professor at Rutgers New Jersey Medical School.

Roger W. Howell

Roger W. Howell, Ph.D., is Distinguished Professor at Rutgers New Jersey Medical School and Robert Wood Johnson Medical School, New Brunswick, NJ, USA.