IL-12 abrogates mechanisms of immune suppression by B-ALL

• Published in: The Journal of immunology (1950) 2021-05, Vol.206 (1_Supplement), p.29-29.03
• Main Authors: Hunter, Rae, Henry, Curtis J., Porter, Christopher
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.29.03

Despite major advance in therapeutic options for treating patients with acute lymphoblastic leukemia (ALL), including the use of immunotherapies, 15–20% of patients still succumb to disease. Given the high mortality rates, particularly in the context of immune-based therapies, there is still a knowledge gap regarding how leukemia cells evade immune surveillance. In published studies, we have shown that interleukin-12 (IL-12) secreted by B-leukemia cells stimulate T-cell mediated immunity. We found that recombinant IL-12 treated WT and Rag1−/− mice, which lack B- and T-cells but still have innate immune cells, had prolonged survival as compared to untreated mice. These results demonstrate that IL-12 increases the anti-leukemia immunosurveillance capacity of innate and adaptive immune cells. Mechanistically, we observed when T-cells were stimulated in ALL supernatant in vitro there is a reduction in the surface expression of the T-cell activation marker, CD44, and marker of degranulation, CD107b. Macrophages co-cultured with leukemia cells were also unable to significantly upregulate the activation markers, CD80 and CD86, compared to macrophages in media alone. We then explored combination therapeutics in vitro to override ALL immune suppression. Considering the potency of IL-12 alone and Blinatumomab, a bispecific T-cell engager (BiTE) antibody used to treat patients with relapsed and refractory disease, we determined how combining these therapies impacted B-ALL cytotoxicity when cultured with T-cells. Impressively, IL-12 augmented the efficacy of Blinatumomab resulting in more T-cell mediated killing of leukemia cells. Our results demonstrate the therapeutic potential of IL-12 as a treatment for ALL.