The Endless Saga of Monocyte Diversity

Abstract

Cancer immunotherapy relies on either restoring or activating the function of adaptive immune cells, mainly CD8 + T lymphocytes. Despite impressive clinical success, cancer immunotherapy remains ineffective in many patients due to the establishment of tumor resistance, largely dependent on the nature of tumor microenvironment. There are several cellular and molecular mechanisms at play, and the goal is to identify those that are clinically significant. Among the hematopoietic-derived cells, monocytes are endowed with high plasticity, responsible for their pro- and anti-tumoral function. Indeed, monocytes are involved in several cancer-associated processes such as immune-tolerance, metastatic spread, neoangiogenesis, and chemotherapy resistance; on the other hand, by presenting cancer-associated antigens, they can also promote and sustain anti-tumoral T cell response. Recently, by high throughput technologies, new findings have revealed previously underappreciated, profound transcriptional, epigenetic, and metabolic differences among monocyte subsets, which complement and expand our knowledge on the monocyte ontogeny, recruitment during steady state, and emergency hematopoiesis, as seen in cancer. The subdivision into discrete monocytes subsets, both in mice and humans, appears an oversimplification, whereas continuum subsets development is best for depicting the real condition. In this review, we examine the evidences sustaining the existence of a monocyte heterogeneity along with functional activities, at the primary tumor and at the metastatic niche. In particular, we describe how tumor-derived soluble factors and cell-cell contact reprogram monocyte function. Finally, we point out the role of monocytes in preparing and shaping the metastatic niche and describe relevant targetable molecules altering monocyte activities. We think that exploiting monocyte complexity can help identifying key pathways important for the treatment of cancer and several conditions where these cells are involved.

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…Strong evidence indicates that the accumulation of macrophages in tumors is due to the continuous recruitment of monocytes from the circulation in response to tumor-derived factors (TDFs). These TDFs are key mediators in the crosstalk between monocytes and tumor cells and include colony-stimulating factor-1 (CSF-1), several C−C chemokine ligands, such as CCL2, also known as MCP-1 and VEGF [75,76]. CCL2 has been described as the major TDF involved in monocyte recruitment, through the CCL2-CCR2 axis.…”

“…CCL2 has been described as the major TDF involved in monocyte recruitment, through the CCL2-CCR2 axis. Hence, blockade of CCR2 can suppress the accumulation of TAMs in tumors [75]. CCR2 inhibitors and anti-CCL2 antibodies have shown efficacy in reducing tumor growth and metastasis in several pre-clinical murine models [76].…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…Monocytes are separated from granulocytes and lymphocytes in automated cell analysers based on their larger size, as well as their non-lobular nucleus and smaller/different granules when compared to granulocytes. Monocyte parameters used in routine clinical practice are their concentration in peripheral blood (absolute numbers), the percentage of monocytes among circulating leukocytes (relative values), and the monocytes-to-platelets ratio (MPR) [94], but the latter is not in clinical use in…”

The Engagement Between MDSCs and Metastases: Partners in Crime

“…Indeed, in both melanoma and liver cancer, PMN-MDSClike cells can increase tumor cell retention and transendothelial migration by integrin (MAC-1)/ICAM-1 interaction (130,131). Finally, both neutrophils and inflammatory monocytes (iMos), that in cancer setting resemble MDSCs (132), can physically associate with cancer cells supporting their extravasation (133).…”