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.

Keywords: metastatic niche; monocyte continuum; monocytes heterogeneity; primary tumor; targeting of monocytes.

Figure 1

Layout depicting the monocyte lineage precursors (on top), the monocyte subsets in the peripheral blood (center), and monocyte fate in cancer tissues. Indicated are relevant surface markers, transcription factors, secreted cytokines, intracellular mediators, and relevant metabolic pathways. Continuous lines indicate events occurring during normal myelopoiesis while shaded lines indicate events in emergency myelopiesis (e.g., cancer and inflammation). Briefly, under steady state cMop precursors originate both inflammatory (1) and patrolling (2) monocytes, both in humans and mice. However, it has been reported that during emergency myelopoiesis cMop precursors can also differentiate into M-MDSC (3) and into not yet defined immature cells (4). Particularly, during infection, inflammatory monocytes acquire a trained phenotype (5) and also switch into Ly6C^int cells (6) only identified in mice and with not fully defined function, transcriptional regulators, and markers. During fibrosis a novel subset of monocytes, so called SatM (8), have been characterized, in mice, defined as Ly6C⁺ and expressing proteins typical of the neutrophil granules (MPO and NE). These cells, together with neutrophil-like monocytes (7), found in peripheral blood of mice during microbial infection and in the bone morrow in steady-state condition, originate from GMP/FcεRI⁺ precursors cells in the bone marrow. In pathological conditions, like cancer, inflammatory monocytes infiltrating the tissue give rise to TAM (9) which in turn represent a fultifaced population of macrophages. Additionally, inflammatory monocytes can also differentiate into classical DC (10) expressing the costimulatory molecules CD80 and CD86 and TipDC (11) expressing high level of NOS2 and TNFα.