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The Use of Chelated Radionuclide (Samarium-153-Ethylenediaminetetramethylenephosphonate) to Modulate Phenotype of Tumor Cells and Enhance T Cell–Mediated Killing

Authors' Affiliations: ¹ Laboratory of Tumor Immunology and Biology and ² Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, and ³ Nuclear Medicine Department, NIH, Bethesda, Maryland; ⁴ Cytogen Corporation, Princeton, New Jersey; and ⁵ Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive, Room 8B09, Bethesda, MD 20892. Phone: 301-496-4343; Fax: 301-496-2756; E-mail: js141c{at}nih.gov.

Purpose: Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell–mediated killing.

Experimental Design: Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate (¹⁵³Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to ¹⁵³Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to ¹⁵³Sm-EDTMP rendered LNCaP cells more susceptible to T cell–mediated killing.

Results: Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to ¹⁵³Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to ¹⁵³Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1.

Conclusions: Doses of ¹⁵³Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that ¹⁵³Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing.