Immune Signaling Therapies In MDS

Over the past decade, the advances in targeted and large-scale next-generation sequencing (NGS) have helped myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) diagnosis, allowing for a refinement of prognostic stratification and targeted treatment. However, the prognosis of higher risk (HR) MDS and of AML with unfavorable features, such as older age, antecedent myeloid disorder, adverse genetic risk, and concurrent gene mutations, is still unfavorable. Indeed, the median overall survival  of MDS patients at very high risk is 0.8 years. In recent years, significant efforts have been made to develop immune therapies for blood cells with abnormal growth. 

Immune System Dysfunction in AML/MDS

Alterations of the immune system can impact the disease development of AML and MDS by altering the delicate balance between smoldering inflammation, immune defense against new organisms, and new alterations to the DNA in promoting or suppressing mutations that produce cancer cells. The bone marrow microenvironment of MDS is characterized by disturbing the immune system cells, with a decrease of some cellular subtypes, such as type 1 innate lymphoid cells (ILC1), as well as an increase in other cell types, that enhance the danger-associated molecular pattern stimulation of caspase-1, which promotes cell death by secreting granzyme B and interleukin 10 (IL-10) and by fostering signaling of toll-like receptor (TLR), CD33, and CXCR2. ILC1 dysfunction has also been observed in AML. 

AML blasts avoid immune surveillance by altering the immune microenvironment through multiple mechanisms, including increased response of immune checkpoints and suppressed stimulus response of human leukocyte antigen (HLA) class I and II. 
Alterations of both innate and adaptive immune responses play a prominent role in the development of AML and MDS, suggesting potential new targets for immunotherapy. 
Innate immune response is the defense system that you have had since birth, what the body knows to be a threat. The adaptive immune response is what the body learns for the first time to attack. 

Immune system regulators 

Immune system regulators are emerging as significant targets for immunotherapy in hematological malignancies. Immune system regulators tested for AML and MDS therapy include CD47, immune checkpoints, and TLR2.

Immune checkpoints are regulators of crucial processes in the immune system as they modulate the signaling pathways responsible for the immune’s system ability to resist harming agents by preventing the immune-mediated destruction of cells. Thus, the primary role of immune checkpoints is to protect tissues from damage when the immune system responds to pathogens and to maintain tolerance to autoantigens preventing autoimmunity. This is mainly achieved by regulating the activation of effector T cells. A primary mechanism through which tumors escape from the immune system is the engagement of immune checkpoints by overexpressing their cell signaling. Therefore, immune checkpoint inhibitors have therapeutic potential against cancer cells as single agents and in combination with hypomethylating agents (HMAs). 

Indeed, hypomethylating agents can modulate the programmed cell death protein AML/MDS patients by modifying gene expressions at specific sites, leading to an overexpression of the checkpoint. This increased expression may be associated with resistance to therapy. 

Conclusions 

Integrating several immunotherapy strategies in AML and MDS treatment still requires large randomized clinical trials to assess these new medicines' true benefit and safety. In addition, the precise positioning and sequencing of the different mAbs under investigation for AML and MDS needs to be defined. Finally, and perhaps most importantly, given a precision medicine approach for AML and MDS immunotherapy, the future studies should also aim to identify molecular predictors of treatment response to a given mAb. This will allow for a biologically rational choice of a specific immunotherapy strategy for the individual patient with AML or MDS.