Engineered murine IL-21-secreting leukemia cells induce granzyme B⁺ T cells and CD4⁺CD44⁺CD62L^- effector memory cells while suppressing regulatory T cells, leading to long-term survival

We have explored the use of an IL-21 cell-based anti-leukemia treatment in a mouse model of acute lymphoblastic leukemia. 70Z/3 leukemia cells, engineered to secrete IL-21 and injected into the peritoneum of syngeneic mice, induced a strong anti-leukemia response resulting in 100% survival. Mice that mounted an IL-21-induced anti-leukemia immune response were immune to the parent cell line (no IL-21) when rechallenged.Above a certain threshold, IL-21 secretion correlated with improved survival compared to mice injected with parent 70Z/3 cells. IL-21 was detected in serum with peak levels on day 7, correlating with the maximum expansion of IL-21-secreting 70Z/3 cells which subsequently were eliminated. Mice injected with IL-21-secreting leukemia cells had elevated numbers of granzyme B⁺ CD4⁺ and CD8⁺ T cells in the peritoneum, compared to mice injected with the parent cell line. Regulatory T cells, which increased greatly in 70Z/3-injected mice, failed to do so in mice injected with IL-21-secreting cells. Upon rechallenge, IL-21-primed mice went through a secondary immune response, primarily requiring CD4⁺ T cells, triggering a significant increase of CD4⁺CD44⁺CD62L^- effector memory T cells. Adoptive transfer of T cells from IL21-primed/rechallenged hosts into naïve mice was successful, indicating that IL-21-primed antigen-experienced T cells convey immunity to naïve mice.Our study shows that delivery of IL-21 in a cell-based anti-leukemia protocol has the potential to induce a potent immune response leading to cancer elimination and long-term immunity-properties which make IL-21 an attractive candidate for cancer immunotherapy. Protecting against tumor antigens as well as improving cancer immunity is justified, as current strategies are limited.