Recombinant Human Prolactin Improves Antitumor Effects of Murine Natural Killer Cells in vitro and in vivo

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Abstract
Objective: To verify the effect of prolactin on natural killer (NK) cells in vivo and its implications for NK cell immunotherapy. Methods: Recombinant human prolactin (rhPRL; 30 µg, i.p.) was administered to BALB/c mice and severe combined immunodeficiency (SCID) mice 1 day before harvesting splenocytes for 51Cr release assay to examine the effects of rhPRL on NK cells of normal mice. rhPRL (10 µg, i.p., every other day for a total of 5 injections) was administered to BALB/c mice after syngeneic bone marrow transplantation (SBMT) to determine its effects on NK cell reconstitution. CT26 tumor cells were injected into BALB/c mice intravenously on day 0, and interleukin (IL)-15-cocultured activated syngeneic NK cells (IL-15-NK) from SCID mice were intravenously injected into tumor-bearing BALB/c mice on day 1. The improvement of antimetastasis effects and survival of tumor-bearing mice by rhPRL were checked. Results: BALB/c and SCID mice receiving one rhPRL injection exhibited a significant increase in cellular cytotoxicity against YAC-1 target tumor cells; the specific lysis was enhanced from 12.5 to 17.3% in BALB/c mice and from 27.8 to 51.2% in SCID mice. BALB/c mice continuously receiving rhPRL injections exhibited significant increases in NK cell (DX5-positive) contents and cellularity in both the bone marrow and spleen in the SBMT model. The bone marrow NK cell contents were improved from 1.53 to 3.13% after rhPRL injection. NK cells from SCID mice were then cultured with recombinant human IL-15 (rhIL-15; 6,000 IU/ml), rhPRL (10 ng/ml) or rhIL-15 plus rhPRL for 25 days. The cytotoxicity and cellularity were enhanced by rhPRL when tested on day 10, when comparing the rhIL-15 plus rhPRL group with the rhIL-15 group or rhPRL group, respectively. In the adoptive cellular immunotherapy study, the IL-15-NK plus IL-15 plus rhPRL group showed significantly lower numbers of lung metastases and longer survival than the IL-15-NK plus IL-15 group; the mean survival interval was prolonged from 31.5 to 53.7 days. Conclusion: These results indicate that rhPRL is possibly an important regulator of NK cells and a potential biologic product for immunotherapy.