Overcoming resistance to immune checkpoint inhibitor therapy in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by molecular, immunological, and clinical heterogeneity and this has been reflected with changing paradigms in the treatment landscape of AML in recent years. Despite high remission rates with conventional chemotherapy regimens, most patients eventually relapse and have disappointing outcomes in the relapsed setting, with estimated 5-year overall survival rates ranging from 10-15%. Immune checkpoint inhibitors (ICIs) restrain T-cell suppressive signals delivered through cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways and promote antitumor immune responses and these agents have been explored successfully in the treatment of many malignancies. Although ICIs have demonstrated long-term clinical benefit in solid tumors such as melanoma or lung cancer, AML has historically been considered an immunologically "cold" tumor and responses have been less robust. Furthermore, the impact of T-cell functional states and the tumor microenvironment in response to standard chemotherapy regimens, molecularly targeted therapies, and immunotherapies is poorly understood. Recent advances in multimodal omics technologies have deepened our understanding of the dynamic cellular interactions at the AML immune interface and immune gene expression profiling can potentially be integrated with clinically validated molecular prognosticators to further stratify AML into potential tumor microenvironment subgroups that could more aptly respond to ICIICIs to reinvigorate dysfunctional T cells and modulate cytotoxicity. This review will attempt to summarize recent discoveries on T-cell functional states in AML and their impact on response to ICIICIs as well as acquired mechanisms of resistance to ICIICIs. Furthermore, strategies to potentially overcome resistance to ICIICIs in the immune-based treatment of AML will be highlighted to provide an outlook for future strategies.