Feifei Zhao

Intratumoral heterogeneity can affect the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse. Whereas the role of cell-extrinsic factors has been described for AML relapse, whether interactions between cancer cells affect chemoresistance is not fully known. In this study, we demonstrated that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. This suppression is mediated in part by both type I and type II intra-leukemic interferon signaling and dependent on BST2. Importantly, blocking antibodies to type II interferon receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting interferon signaling as a potential therapeutic target to counter chemoresistance.Significance:AML presents a significant challenge in clinical management due to its poor prognosis and high rates of relapse following chemotherapy. Using multiple models of primary human AML, we demonstrate that competitive interactions between leukemia cells affect clonal dynamics and therapy resistance, thereby identifying a potential strategy to improve patient outcomes.See related commentary by Papaioannou and Aifantis, p. 18

Supplementary Table 1 shows List of genes for gene set enrichment analysis Supplementary Table 2 shows Sequences of gRNA Supplementary Table 3 shows List of antibody Supplementary Table 4 shows Sequences of primers and probes

Supplementary Figure 1 shows Suppressed leukemia cells maintain disease-initiating capacity. Supplementary Figure 2 shows iAML isogenic competition model with fluorescent G0 reporter. Supplementary Figure 3 shows Oxidative phosphorylation does not account for suppression Supplementary Figure 4 shows IFN signaling inhibits suppressed samples Supplementary Figure 5 shows BST2 contributes to IFN-mediated AML suppression. Supplementary Figure 6 shows IFN signaling is associated with chemoresistance in experimental models. Supplementary Figure 7 shows IFN signaling is associated with chemoresistance in primary AML patient samples. Supplementary Figure 8 shows Blocking IFN signaling affects cycling and chimerism of patient samples.

In vivo TR-APC induction drives oligoclonal T cell expansion

In vivo TR-APC induction results in no observable off-target toxicity

Summary of clinical features of primary B-ALL specimens

In vivo TR-APC induction results in expansion of activated and memory T cells, and decreased frequency of Tregs

Primary B-ALL TR-APCs can be generated via exogenous cytokine stimulation

Primary B-ALL-derived TR-APCs activate T cells in an MHC-restricted manner according to the inflammatory milieu

In vivo doxycycline administration results in significant TR-APC induction throughout tumors