Targeting the innate immune system as immunotherapy for acute myeloid leukemia

Abstract

Because of its disseminated nature and lack of tumor-draining lymph nodes, acute myeloid leukemia (AML) likely employs unique immune evasion strategies as compared to solid malignancies. Targeting these unique mechanisms may result in improved immunotherapeutic approaches. Emerging data suggest that a specific dendritic cell (DC) subset, CD8α DCs, may be responsible for mediating tolerance in AML and thus targeting the innate immune system may be of benefit in this disease. Promising immune targets include the toll-like receptors, calreticulin/CD47, the stimulator of interferon genes pathway, and signal transducer and activator of transcription 3 (STAT3). However, it is becoming clear that compensatory mechanisms may limit the efficacy of these agents alone and thus rationale combinations of immunotherapies are warranted. This review discusses the potential immune evasion strategies in AML, as well as discussion of the promising innate immune targets, both alone and in combination, for this disease.

Keywords: STAT3; acute myeloid leukemia; calreticulin; innate immune system; toll-like receptors; type I interferon.

Figure 1

Pathways of potential immune targeting in AML. (A) Innate immunity may be targeted in AML through activation of the STING, TLR (specifically TLR-3) and CD40 receptors. Strategies to enhance calreticulin exposure on AML cells, combined with CD47-blocking antibodies may also be effective. Lastly, STAT3 signaling appears to inhibit the innate immune response, including hampering the effect of TLR9, and inhibition of STAT3 signaling in AML cells leads to differentiation to antigen presenting cells (APCs) with an activated DC phenotype. Activation of the innate immune system, either by stimulating activating pathways or blocking inhibitory pathways, ultimately leads to increased IFN-γ production by CD8⁺ T cells. (B) Increased IFN-γ resulting from activating of the innate immune system may lead to compensatory up-regulation of other immune evasion pathways, such as PD-L1, indoleamine-2,3-dioxygenase (IDO), and regulatory T cells (Treg). While innate immune activation will be critical to induce anti-leukemia T cell priming, combination therapy targeting compensatory pathways will be key in eliciting a clinically significant anti-leukemia immune response.