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Harnessing anti-cancer immunity to vaccinate against treatment failure and relapse

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Recent studies have found that an immunosurveillance system normally prevents the development of cancer. Pre-malignant cells must either hide from or reprogram the immune system to avoid recognition. Immunotherapy has been highly successful in a subset of adult cancers; however, immunotherapeutic solutions for pediatric cancers have been particularly limited. Typically, successful treatment continues to involve the use of highly toxic drugs, which are immunosuppressive and often cause life-long complications. Furthermore, nearly 20% of childhood cancer patients do not survive long-term. Among survivors, 15% develop heart dysfunction from the use of anthracyclines, which serve as backbone chemotherapeutics. This situation has remained largely unchanged for decades, indicating an urgent need for new treatments.

We and others have recently found that rare, tumor-initiating leukemia stem cells (LSCs) play a unique role in immune evasion and escape and thus the failure of the immunosurveillance system and immunotherapies. Two key genetic pathways that are frequently mutated in cancer, termed Wnt/ß-catenin and PI3K/Akt, interact to drive stem cell self-renewal and resistance to cancer therapies, including immunotherapy. Given these roles, we sought to target the interaction between them, specifically the activation of ß-catenin by Akt. High-throughput screening surprisingly identified anthracyclines such as doxorubicin (DXR), highly toxic chemotherapeutics when used at typical clinical doses, as the top screen ‘hits’. Importantly, DXR’s on-target effect occurred well below the generally toxic dose. Unlike current clinical practice of using anthracyclines as broadly poisonous agents, we repurposed them to inhibit Akt:ß-catenin interaction and specifically target therapy-resistant leukemia stem cells (LSCs), which are responsible for relapse.

Interestingly, we found that this targeted use of anthracyclines, unlike the immunosuppressive chemotherapeutic dose, largely acts through cancer-targeting immune cells. This occurs in part because Akt-activated ß-catenin induces expression of multiple immune checkpoint (IC) genes, which confers therapy-resistance on LSCs, but targeted anthracycline treatment inhibits this. Furthermore, low-dose anthracycline treatment, unlike the clinical dose, can stimulate immunogenic cell death (ICD). ICD of cancer cells, in contrast to other forms of cell death, can induce an effective anti-cancer immune response, which can effectively immunize the patient to the cancer and prevent recurrence. While anthracyclines are known to induce ICD in the laboratory, clinically this effect is not observed. This is due not only to immunosuppression caused by high doses but also the fundamentally unique response by both LSCs and the immune system to high vs. low doses, and we are currently investigating these responses at the cellular and functional level.

Here, our central hypothesis, supported by our preliminary data, is that systemic immunological changes representing restoration of anti-cancer immunosurveillance is induced by low dose/targeted anthracycline treatment. However, the precise mechanisms of how LSCs are targeted and eliminated by the immune system are unclear. Furthermore, the diversity and identity of immune cells involved remains obsure. Here, we propose to complement ongoing studies to overcome this limitation by conducting single-cell transcriptomics for high resolution of cellular differences and improved understanding of individual cell function in the context of the evolving leukemic microenvironment under therapeutic stress vs. immune reactivation.

Specific Aim 1: Determine the transcriptomic changes among cellular populations during leukemogenesis. Our recent publication (Perry et al., Nat. Cell Biol. 2020) shows that LSCs exhibit unique properties of immune escape, but how they dynamically change and interact with an evolving immune system during leukemia development and progression is poorly understood. Using stem cell activated ß-catenin/Akt leukemia mice and single-cell transcriptomics, we will determine the dynamic changes in leukemia and normal stem cells, blast cell progeny of LSCs, and immune cells during leukemia initiation and progression.

Specific Aim 2: Determine the repertoire and transcriptome of immune cells that target LSCs. Our preliminary data reveals that LSCs exhibit unique properties of immune escape that are reduced by inhibiting Akt-activated ß-catenin using low-dose but not high-dose DXR. We will determine the quantity and diversity of immune cells that target therapy-resistant LSCs during treatment with targeted/low-dose vs. chemotherapeutic (i.e. high-dose) anthracycline treatment.

Specific Aim 3: Analyze the response of pediatric leukemia and immune cells to low dose anthracycline treatment. A currently approved clinical trial at Children’s Mercy is collecting diagnostic, day 8 post-low dose anthracycline treatment, and day 29 post-chemotherapy samples from pediatric leukemia patients. We will determine the immune and leukemia response to low dose anthracycline treatment at the single cell level.

In coordination with ongoing cellular and functional studies, these aims will help identify critical immune components and novel cellular pathways that can be targeted to enhance anti-cancer immune responses.
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