Targeting immune checkpoints in hematological malignancies

Abstract

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.

Keywords: Hematological malignancy; Immune checkpoint molecule; Immunotherapy; Tumor microenvironment.

Fig. 1

CTLA-4-mediated immune regulation. Schematic illustrating T cell-intrinsic (left) and extrinsic regulation by CTLA-4 (right). Left: CTLA-4 is upregulated on activated T cells and competes with the CD28 co-stimulatory receptor due to its higher affinity for CD80/CD86. Right: CTLA-4 plays a critical role in Treg-mediated immune regulation. The CTLA-4/CD80 interaction between Treg/APCs induces indoleamine 2,3-dioxygenase (IDO), a key enzyme that suppresses T cells by tryptophan deprivation. Additionally, Tregs down-modulate CD80/86 expression on APCs by transendocytosis

Fig. 2

PD-1-mediated immune regulation. Under low expression levels of PD-L1, CD80 restricts PD-L1 function by forming the PD-L1/CD80 cis-heterodimer. The PD-L1/CD80 cis-heterodimer prevents the PD-1/PD-L1 trans-interaction, whereas the ability to bind to the CD28 co-stimulatory receptor is retained (left). Upregulation of PD-L1 on APCs allows the PDL-1/PD-1 trans-interaction, leading to SHP2-dependent negative regulation of the CD28 signaling pathway as well as transcriptional repression of TCR-induced effector genes (right)

Fig. 3

Negative regulators of T cell immunity other than PD-1 and CTLA-4. Schematic illustrating receptors and their ligands regulating T cell immunity. Multiple immune checkpoint molecules are differentially implicated in the regulation of activated T cells including LAG-3, TIM-3, and TIGIT. Plus and minus signs denote stimulatory and inhibitory signaling respectively. Single-headed and double-headed arrows denote uni-directional and bi-directional signaling respectively. APC, antigen-presenting cell; TCR, T cell receptor; LAG-3, lymphocyte-activation gene 3; CD112R, CD112 receptor; MHC, major histocompatibility complex; FGL1, fibrinogen-like protein 1; DNAM-1, DNAX accessory molecule 1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TIM-3, T cell immunoglobulin mucin-3

Fig. 4

Negative regulators of innate anti-tumor immunity. Schematic illustrating receptors and their ligands regulating anti-tumor immunity by NK cells (top) and macrophages (bottom). In NK cells, inhibitory receptors that recognize MHC class 1 molecules are recognized as a potential target to enhance NK cell-mediated cytotoxicity against tumors. Targeting macrophage phagocytosis checkpoints has also emerged as a potential approach in combination with various cancer mAb therapies due to its potential in enhancing the elimination of antibody-coated tumor cells. An immunosuppressive metabolite, adenosine, also potently inhibits innate and adaptive anti-tumor immunity. ADCP, antibody-dependent cellular phagocytosis; ADCC, antibody-dependent cellular cytotoxicity; DNAM-1, DNAX accessory molecule 1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; NKG2A, NK group 2 member A; KIRs, killer-cell immunoglobulin-like receptors; HLA, human leukocyte antigen; MHC, major histocompatibility complex; LILRB1, leukocyte immunoglobulin-like receptor B1; SIRPα, signal regulatory protein α, Siglec-10, Sialic acid-binding Ig-like lectin 10