Vaccine cells derived from cancer stem cells expressing Interleukin-15 and its receptor inhibit tumor growth

Background: Interleukin-15 (IL-15) is a powerful activator and inducer of NK cells and cytolytic CD8+ T cells. IL-15 also activates and expands CD8+ memory T cells without stimulating immunosuppressive CD4+CD25+ T regulatory cells. As such, IL-15 may be useful as an immunotherapy for cancer. In an effort to enhance antitumor activity and reduce systemic side effects, we studied an approach using a tumor vaccine enriched for cancer stem cells (CSCs) expressing murine (m) IL-15 and its receptor (mIL-15Rα). Methods: Lentiviral vectors expressing the wild type or optimized (opt) cDNA sequences for mIL-15 and/or mIL-15Rα under the control of the human EF-1 promoter were generated and used to transduce TC1 mouse lung cancer cells. The TC1 cells were cultured under low serum conditions to generate tumor spheroids enriched for CSCs. Results: The transduced TC1 cells demonstrated the expected mRNA transcripts. On flow cytometry only the cells transduced with mIL15Rα in combination with mIL-15 showed surface expression of mIL-15, while cells transduced with mIL-15 or mIL-15Rα constructs did not. When co-cultured with the transduced tumor spheroids or incubated with supernatants from these TC1 cells, CTLL-2 murine T cells demonstrated proliferation indicating that the cloned cDNAs expressed functional proteins. The vector demonstrating the greatest stimulation of CTLL-2 cells expressed both the mIL-15Rα and mIL-15opt sequences and demonstrated suppressed TC1 tumor growth in vivo. Conclusion: CSCs expressing mIL-15Rα and mIL-15 stimulated proliferation of T cells in vitro and demonstrated inhibited tumor growth in mice. In vivo tumor vaccination studies are in progress.