GSE201765
The Impact of T cell Immunity on Chemotherapy Response in Childhood Acute Lymphoblastic Leukemia
Although acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how and which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T cell immunity on ALL chemotherapy outcomes. Using murine BCR-ABL1 ALL model, we showed that loss of total T cells, CD4 cells, or CD8 cells in the host drastically increased leukemia relapse following dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation Type I immunity-related cytokine signaling linked to long-term leukemia remission in mice. Consistent with these observations, IFNG and IL12 directly modulated dasatinib anti-leukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T cell abundance with treatment outcomes. Together, these results suggest that T cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes. Overall design: To explore the mechanisms underlying host immune response against ALL, we performed molecular profiling experiments in immunocompetent mice to compare features that distinguish those that did vs. did not relapse after dasatinib therapy. To this end, we collected peripheral blood leukocytes one week after the initiation of dasatinib treatment from all mice, and cryo into liquid nitrogen. At that time, they were all in remission and then continued dasatinib treatment for 4 additional weeks. Mice were retrospectively classified as “cured” or “relapsed” based on their survival status at 100 days post leukemia inoculation, i.e., the “cured group” and the “relapsed group”. After 100 days of the experiment, six mice remained in remission, and six mice relapsed. Cells were thawed from liquid nitrogen, and live cells were collected by BD Biosciences Aria cell sorters. We mixed the peripheral blood leukocyte from three mice as one scRNA-seq sample. Thus, we have two cured and two relapsed samples in total.