Immune checkpoint blockade (ICB) therapies such as anti-programmed death 1 (PD-1) and anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) have dramatically transformed treatment in solid tumor oncology. While immunotherapeutic approaches such as stem cell transplantation and anti-cancer monoclonal antibodies have made critical contributions to improve outcomes in hematological malignancies, clinical benefits of ICB are observed in only limited tumor types that are particularly characterized by a high infiltration of immune cells. Importantly, even patients that initially respond to ICB are unable to achieve long-term disease control using these therapies. Indeed, primary and acquired resistance mechanisms are differentially orchestrated in hematological malignancies depending on tumor types and/or genotypes, and thus, an in-depth understanding of the disease-specific immune microenvironments will be essential in improving efficacy. In addition to PD-1 and CTLA-4, various T cell immune checkpoint molecules have been characterized that regulate T cell responses in a non-redundant manner. Several lines of evidence suggest that these T cell checkpoint molecules might play unique roles in hematological malignancies, highlighting their potential as therapeutic targets. Targeting innate checkpoint molecules on natural killer cells and/or macrophages has also emerged as a rational approach against tumors that are resistant to T cell-mediated immunity. Given that various monoclonal antibodies against tumor surface proteins have been clinically approved in hematological malignancies, innate checkpoint blockade might play a key role to augment antibody-mediated cellular cytotoxicity and phagocytosis. In this review, we discuss recent advances and emerging roles of immune checkpoint blockade in hematological malignancies.

Highlights d RSPO-LGR4 is essential for stem cell self-renewal in a subset of AML d LGR4 promotes aberrant self-renewal through cooperation with HOXA9 d RSPO3 acts as a stem cell growth factor to sustain proliferation of AML patient blasts d Clinical-grade anti-RSPO3 impairs LSC self-renewal in patient-derived xenografts

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