Tuning the Tumor Myeloid Microenvironment to Fight Cancer

Abstract

The tumor microenvironment (TME) of diverse cancer types is often characterized by high levels of infiltrating myeloid cells including monocytes, macrophages, dendritic cells, and granulocytes. These cells perform a variety of functions in the TME, varying from immune suppressive to immune stimulatory roles. In this review, we summarize the different myeloid cell populations in the TME and the intratumoral myeloid targeting approaches that are being clinically investigated, and discuss strategies that identify new myeloid subpopulations within the TME. The TME therapies include agents that modulate the functional activities of myeloid populations, that impact recruitment and survival of myeloid subpopulations, and that functionally reprogram or activate myeloid populations. We discuss the benefits, limitations and potential side effects of these therapeutic approaches.

Keywords: dendritic cell (DC); immune checkpoint blockade (ICB); macrophage; monocytes; myeloid cells; myeloid tuning; tumor associated macrophage (TAM); tumor micoenvironment.

Figure 1

Summary of the different subtypes of myeloid cells present in the TME, their ontogeny and development, their survival and trafficking requirements, and their human and mouse nomenclatures including transcription factors and cell surface markers. The “Others” myeloid cells in the last row represent the granulocytes. “Lineage⁻” is defined as CD3⁻CD14⁻CD16⁻CD19⁻ for the human nomenclature and CD3⁻NKp46⁻B220⁻ for the murine nomenclature.

Figure 2

Cartoon depicting the six “Pillars of Myeloid Tuning” and the myeloid targets within each category. The myeloid tuning strategies affecting the Composition of the TME include targets modulating Recruitment (CCL2-CCR2/5, CSF1-CSF1R, CXCL8-CXCR1/2; CXCL12-CXCR4, VEGF-VEGFR, Endothelins), Proliferation (FLT3L-FLT3, TLRs, CD40-CD40L), and Survival (CSF1R, TRAIL/Caspase 8, VEGF, c-kit). The myeloid tuning strategies altering the Function of the TME include targets inducing Differentiation (CSF1, GM-CSF, G-CSF, Retinoic Acid Receptor ATRA), Reprogramming (Histone Deacetylase, CSF1R, MARCO, Arginase, PI3Kγ), and Activation (CD47-SIRPα, A2AR, CD73/CD39, STING, TLRs, CD40, Arginase). The indicated myeloid targets in each category are not comprehensive.