Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

Abstract

Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.

Keywords: CAR-M; Dendritic cells; Myeloid; Myeloid-derived suppressor cells (MDSCs); Polarization; Proliferation; Recruitment; Reprogramming; Tumor microenvironment; Tumor-associated macrophages (TAMs).

Fig. 1

Myeloid cells in the TME: friend or foe? A. Myeloid cells can be molded by the TME or therapeutic strategies to exert either pro-tumor or anti-tumor functions. TAMs, tolerogenic DCs, neutrophils, and MDSCs mainly foster cancer progression through supporting tumor cell transition and proliferation, promoting metastasis through enhanced vascularization and preparation of metastatic niche, as well as mediating immunosuppression, through the secretion of soluble factor, extracellular vesicles or direct ligand–receptor interaction. TAMs, DCs, and neutrophils can be programmed toward an anti-tumor phenotype. cDC1s and cDC2s are major APCs that present tumor-associated antigens to T cells and prime T cell responses. TAMs can be reprogrammed to serve as APCs. Both TAMs and DCs, once properly activated, express cytokines such as type I IFN, CXCL9, and CXCL10 to recruit T cells into the TME. Neutrophils can perform direct cancer killing through the generation of ROS or indirect killing induced by death signals such as TRAIL and TNF. B. Summary of the cross talk between myeloid cells and tumor cells in the TME. Tumor cells secreted a variety of soluble factors including chemo attractants that recruit myeloid cells. The recruited myeloid cells further amplify these signals and in turn fuel tumor growth and metastasis by producing factors that remodulate surrounding tissue structure, growth factors, and immunosuppressive molecules. Red: anti-tumor effects; Black: pro-tumor effects

Fig. 2

Myeloid-specific targets as immune adjuncts for the management of solid malignancies. Targets were categorized based on their functional role: proliferation, differentiation, recruitment, polarization, functional blockade, cytokine signaling, epigenetic reprogramming, and metabolic reprograming. For cellular therapies, myeloid-specific approaches include dendritic cell vaccines and chimeric antigen receptor macrophages