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.

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

“…So far, there has been no breakthrough in the research of innate immune drugs regarding TLRs, and the selectivity and effectiveness are not clear yet. Emerging immunotherapies were proposed to overcome the primary and secondary resistance to existing immune checkpoint inhibitors, activate effector cells, and target immunosuppressive mechanisms in tumor microenvironment [141,[183][184][185]. More research needs to be explored regarding the mechanisms of the innate immune therapeutic agents.…”

Low TFPI2 expression is associated with poor prognosis and defective immune cell infiltration in breast cancer disease

“…The composition of immune cells in the tumor microenvironment is an important predictor of bene cial survival and therapeutic outcome [41][42][43]. We found that TFPI2 expression was positively correlated with a variety of immune cells, such as CD8+T cells, B cells, cytotoxic cells and NK cells.…”

Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways

“…During the past decade, the explosive growth in macrophage-targeted therapy indicates that the TAM-targeted therapy is an effective antitumor strategy, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or immunotherapy. Most of the preclinical studies and clinical trials have been based on the therapeutic strategies according to their different mechanisms, including those that inhibit mononuclear macrophage recruitment, those that deplete TAMs, and those that reprogram TAMs [ 176 , 177 ]. However, clinical trials specifically designed to modulate or interfere with the self-renewal of TAMs are lacking.…”