Introduction to a review series on oncogenic signaling and immune evasion in hematologic malignancies

Primary and secondary resistance of hematologic malignancies to allogeneic hematopoietic stem cell transplantation (allo-HCT) and other immunotherapies relies on immune escape mechanisms of the leukemia or lymphoma cells. Therefore, a better understanding of how immune escape mechanisms are regulated is key to improving clinical outcomes.

The overarching hypothesis of this review series is that oncogenic signaling can enable hematologic malignancies to evade natural immune surveillance and immunotherapy. Oncogenic signaling and tumor immunology are individual, often separate, research areas, and connecting both areas may help to develop novel rational combination therapies. The series of reviews describes major novel developments in preventing immune escape, for example, by the use of kinase inhibitors to interfere with oncogenic signaling, MDM2 inhibition to increase p53 activity, and epigenetic therapy approaches to enhance major histocompatibility complex (MHC) expression. The authors discuss the biology of leukemia immune escape in the context of the results of recent clinical trials.

• Jayakumar Vadakekolathu and Sergio Rutella, “Escape from T-cell–targeting immunotherapies in acute myeloid leukemia”

• Tilman Brummer and Robert Zeiser, “The role of the MDM2/p53 axis in antitumor immune responses”

• Annalisa Tameni, Cristina Toffalori, and Luca Vago, “Tricking the trickster: precision medicine approaches to counteract leukemia immune escape after transplant”

In contrast to solids tumors, immune checkpoint inhibitors (CPIs) or other antibody-based immunotherapies have not been approved so far for acute myeloid leukemia (AML). A better understanding of the AML microenvironment may help to overcome resistance to these therapies. In agreement with this concept, AML subgroups with high interferon gamma signaling were shown to respond to CD123 × CD3 bispecific dual affinity retargeting (DART) molecules and CPIs. Vadakekolathu and Rutella report advances in our understanding of T-cell exhaustion and senescence in AML. The authors discuss how this knowledge could be translated into opportunities to manipulate the AML microenvironment with the goal to overcome resistance to CPI and other T-cell immunotherapies, in particular in p53-mutated AML.

The review by Brummer and Zeiser discusses the concept that manipulation of MDM2 and p53 could enhance immunogenicity of AML cells with a focus on the p53-mediated upregulation of MHC class I and II expression, the transcription of double-stranded RNA of endogenous retroviruses, and interferon responses upon MDM2 inhibition as well as interleukin-15 production. Also increased sensitivity of AML cells to TRAIL-mediated cytotoxicity exerted by T cells, due to forced induction of TRAIL receptor 1 and 2 expression on AML cells by MDM2 inhibition, is discussed. Independent of the effect on the leukemia cells, the direct effects of MDM2 inhibition or MDM2 deletion on effector T cells are debated in the context of cancer immunotherapy. The preclinical findings are connected to different clinical studies using MDM2 inhibition to enhance antitumor immunity in patients.

Tameni et al summarize current knowledge on AML immune evasion including downregulation or genetic loss of HLA molecules, upregulation of inhibitory ligands on AML cells during relapse after allo-HCT, and epigenetic mechanisms of AML immune escape such as polycomb repressive complex 2 (PRC2), which causes MHC downregulation. Conversely, inhibitors of the PRC2 complex salvaged HLA class II expression on AML cells. This review also focuses on translation of the biological information into clinical studies for AML relapse prevention or treatment with the intention of developing new personalized approaches to improve clinical outcome of patients with AML undergoing allo-HCT.

This review series presents important insights into novel therapeutic strategies to enhance the antileukemia effect of allo-HCT and antibody-based approaches for AML including epigenetic modifiers, kinase inhibitors, CPIs, and bispecific DART molecules. A major goal of this review series is to provide the treating physician with an overview of novel therapeutic targets that have reached clinical testing and may change clinical care.

Conflict-of-interest disclosure: R.Z. has received honoraria from Novartis, Incyte, Sanofi, and Mallinckrodt.