Myeloid cells are abundant in tumors and play diverse roles in coordinating the anti-tumor immune response, thus impacting tumor control. Macrophages have predominantly pro-tumoral functions, with many studies associating macrophage abundance with worsened patient outcome. However, the mechanisms governing monocyte infiltration and differentiation in tumor parenchyma, which subsequently contributes to tumor macrophage abundance, remain poorly understood.
Recently, we identified that tumor cell-intrinsic Snai2 expression correlates with myeloid abundance in a cohort of 116 human and 36 mouse tumor samples. Overexpression of Snai2 in malignant cells was sufficient to drive an increase in tumor monocytes and a decrease in macrophages, remodeling the local myeloid compartment without altering circulating monocyte abundance. Ex vivo tumor spheroid co-culture demonstrated greater monocyte invasion into Snai2-expressing tumor tissue, while in vivo tracking of newly infiltrated monocytes revealed impaired monocyte-to-macrophage maturation in Snai2 tumors.
To explore the mechanism underlying this maturation inhibition, we found that myeloid cells in Snai2 tumors displayed altered motility. Snai2 expression in malignant cells elicited broad transcriptional changes in pathways related to extracellular matrix organization and cell adhesion, suggesting tumor cell remodeling of local tissue architecture may constrain monocyte differentiation. Functionally, Snai2 tumors exhibited altered CD4 T cell abundance and a partial relief of CD8 T cell exhaustion phenotypes, indicating immune remodeling downstream of the myeloid compartment. Preliminary tumor growth data in CCR2null hosts, which have minimal circulating monocytes, is consistent with a model in which reduced monocyte-to-macrophage maturation, rather than monocyte infiltration alone, underlies a decreased growth rate in Snai2 tumors.
Our findings establish malignant cell-intrinsic programs as regulators of monocyte fate within the TME, which impacts both innate and adaptive immune compartments. Our ongoing work aims to define the mechanistic link between tumor cell-driven tissue remodeling and monocyte differentiation, seeking to identify strategies for manipulating myeloid maturation to enhance anti-tumor immunity.