Targeting macrophages in hematological malignancies: recent advances and future directions

Abstract

Emerging evidence indicates that the detection and clearance of cancer cells via phagocytosis induced by innate immune checkpoints play significant roles in tumor-mediated immune escape. The most well-described innate immune checkpoints are the "don't eat me" signals, including the CD47/signal regulatory protein α axis (SIRPα), PD-1/PD-L1 axis, CD24/SIGLEC-10 axis, and MHC-I/LILRB1 axis. Molecules have been developed to block these pathways and enhance the phagocytic activity against tumors. Several clinical studies have investigated the safety and efficacy of CD47 blockades, either alone or in combination with existing therapy in hematological malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoma. However, only a minority of patients have significant responses to these treatments alone. Combining CD47 blockades with other treatment modalities are in clinical studies, with early results suggesting a synergistic therapeutic effect. Targeting macrophages with bispecific antibodies are being explored in blood cancer therapy. Furthermore, reprogramming of pro-tumor macrophages to anti-tumor macrophages, and CAR macrophages (CAR-M) demonstrate anti-tumor activities. In this review, we elucidated distinct types of macrophage-targeted strategies in hematological malignancies, from preclinical experiments to clinical trials, and outlined potential therapeutic approaches being developed.

Keywords: BsAbs; CAR-M; CD24/SIGLEC-10; CD47; CSF1R inhibitor; MARCO; MHC-I/LILRB1/2; Macrophage; PD-1/PD-L1; SIRPα; TLR agonist; Tim-4.

Fig. 1

An overview of normal hematopoiesis and possible immune escape mechanisms for blood cancers: normally, hematopoietic stem cells (HSCs) develop, in a fate-determined manner, into spectrum-specific hematopoietic progenitor cells, which then differentiate into relative terminal cells. The terminal cells maintain stable hematopoietic development. Inevitably, some precancerous cells appear during the development of the hematopoietic system, but are normally cleared by the immune system. However, precancerous cells can develop into various kinds of hematological malignancies when the immune system is compromised by T cells, B cells, NK cells, MDSC, TAM, and so on

Fig. 2

History of discovering phagocytosis-associated checkpoint inhibitors: over the past two decades, a great deal of progress has been made in identifying phagocytosis-associated checkpoints

Fig. 3

Anti-tumor mechanisms of blocking CD47/SIRPα interaction: through blocking the CD47/SIRPα interaction, anti-tumor effects were induced via direct cancer-killing effects, antibody-dependent cellular phagocytosis (ADCP), antigen presentation and T cell immune responses, antibody-dependent cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC)

Fig. 4

Main “Don’t Eat Me” signals discovered so far: The CD47/SIRPα axis, PD-1/PD-L1 axis, MHC-I/LILRB1 axis, and CD24/SIGLEC-10 axis all play significant roles in inhibiting cancer cell engulfment, and disruption of these interactions can enhance the phagocytosis of macrophages

Fig. 5

Current and potential CD47/SIRPα-targeted bispecific antibodies (BsAbs) in hematological malignancies: hematological malignancies can be treated with BsAbs that bind “don’t eat me” signal molecules expressed by macrophages and markers specific to tumor cells

Fig. 6

Processes by which CD19 CAR macrophages specifically recognize, phagocytose, digest, and kill CD19⁺ cancer cells: CD19-CAR macrophages can recognize, engulf, digest, and kill CD19⁺ cancer cells but not CD19⁻ cancer cells