Tumor-associated myeloid cells maintain immunosuppressive microenvironments within tumors. Identification of myeloid-specific receptors to modulate tumor-associated macrophage and myeloid-derived suppressor cell (MDSC) functions remains challenging. The leukocyte immunoglobulin-like receptor B (LILRB) family members are negative regulators of myeloid cell activation. We investigated how LILRB targeting could modulate tumor-associated myeloid cell function. LILRB2 antagonism inhibited receptor-mediated activation of SHP1/2 and enhanced proinflammatory responses. LILRB2 antagonism also inhibited AKT and STAT6 activation in the presence of M-CSF and IL-4. Transcriptome analysis revealed that LILRB2 antagonism altered genes involved in cell cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade effectively suppressed granulocytic MDSC and Treg infiltration and significantly promoted in vivo antitumor effects of T cell immune checkpoint inhibitors. Furthermore, LILRB2 blockade polarized tumor-infiltrating myeloid cells from non–small cell lung carcinoma tumor tissues toward an inflammatory phenotype. Our studies suggest that LILRB2 can potentially act as a myeloid immune checkpoint by reprogramming tumor-associated myeloid cells and provoking antitumor immunity.

One of the mechanisms by which tumor cells evade the immune system is the lack of proper antigen-presenting cells. Improvement in host immunity against tumor cells can be achieved by promoting the differentiation of dendritic cells (DCs) from immature myeloid cells (Gr-1⁺Ly-6C⁺F4/80⁺) that accumulate in the bone marrow and lymphoid organs of mice with large tumor burdens. The enriched immature myeloid cells inhibit T-cell proliferation and tumor-specific T-cell response, which can be reversed by the differentiation of immature myeloid cells or depletion of F4/80⁺ cells. Sorted Gr-1⁺/F4/80⁺ immature myeloid cells differentiated into CD11c⁺ cells that express CD80 and I-A/I-E (MHC class II) in the presence of recombinant murine granulocyte macrophage colony-stimulating factor (GM-CSF). Furthermore, intratumoral gene delivery of GM-CSF not only promoted the differentiation of carboxyfluoroscein succinimidyl ester-labeled immature myeloid cells into CD11c⁺ cells with the characteristics of mature DCs (CD80⁺, I-A/I-E⁺) but also enhanced innate natural killer and adaptive cytolytic T-cell activities in mice treated with interleukin (IL)-12 and anti-4–1BB combination therapy. More importantly, intratumoral delivery of GM-CSF and IL-12 genes in combination with 4–1BB costimulation greatly improved the long-term survival rate of mice bearing large tumors and eradicated the untreated existing hepatic tumor. The results suggest that inducing the maturation of immature myeloid cells, thus preventing their inhibitory activity and enhancing their antigen-presenting capability, by GM-CSF gene therapy is a critically important step in the development of effective antitumor responses in hosts with advanced tumors.

A phase 1/2 clinical trial in patients with chemoresistant triple-negative breast cancer targets the inducible nitric oxide signaling pathway.

Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.