Specialized Pro-Resolving Mediators Mitigate Cancer-Related Inflammation: Role of Tumor-Associated Macrophages and Therapeutic Opportunities

Abstract

Inflammation is a fundamental physiological response orchestrated by innate immune cells to restore tissue homeostasis. Specialized pro-resolving mediators (SPMs) are involved in active resolution of inflammation but when inflammation is incomplete, chronic inflammation creates a favorable environment that fuels carcinogenesis and cancer progression. Conventional cancer therapy also strengthens cancer-related inflammation by inducing massive tumor cell death that activate surrounding immune-infiltrating cells such as tumor-associated macrophages (TAMs). Macrophages are key actors of both inflammation and its active resolution due to their plastic phenotype. In line with this high plasticity, macrophages can be hijacked by cancer cells to support tumor progression and immune escape, or therapy resistance. Impaired resolution of cancer-associated inflammation supported by TAMs may thus reinforces tumor progression. From this perspective, recent evidence suggests that stimulating macrophage's pro-resolving functions using SPMs can promote inflammation resolution in cancer and improve anticancer treatments. Thus, TAMs' re-education toward an antitumor phenotype by using SPMs opens a new line of attack in cancer treatment. Here, we review SPMs' anticancer capacities with special attention regarding their effects on TAMs. We further discuss how this new therapeutic approach could be envisioned in cancer therapy.

Keywords: cancer; inflammation; macrophages; phagocytosis; specialized pro-resolving mediators; tumor microenvironment.

Figure 1

Lipid mediators’ time-course, synthesis and biological actions. Lipid mediators are produced sequentially through action of specific enzymes. Pro-inflammatory lipid mediators (prostaglandins and leukotrienes) are first produced during inflammation initiation. During inflammation resolution, a switch in lipid mediator synthesis occurred and promote SPMs’ synthesis. Each SPM execute its functions by binding to a specific receptor. The receptors for LXB4, RvE2, RvE3, RvD4 have not been characterized yet (–17).

Figure 2

Diversity of macrophages’ phenotypes. (A) Monocytes can be differentiated in vitro either in pro-inflammatory M1-like macrophages or in anti-inflammatory M2-like macrophages upon various external stimuli. M1-like macrophages are involved in microbicidal and tumoricidal activities. M2-like macrophages have pro-resolving functions and are involved in tissue repair. In cancer settings, TAM, associated to a M2-like phenotype, support tumor progression and mitigate tumor response to anticancer treatments through production of proteases, angiogenic and growth factors. (B) During efferocytosis of apoptotic cells, macrophages undergo a reprogramming toward a pro-resolving phenotype. Macrophages receive an important metabolic load from these engulfed cells that induce metabolic modifications such as activation of the putrescine pathway or increased glycolysis that supports actin polymerization and cell clearance. Pro-resolving macrophages express 12/15-LOX and turn off production of pro-inflammatory cytokines for production of IL-10, TGF-β and IFN-β that participate in inflammation resolution.

Figure 3

TAMs execute diverse activities during tumor initiation and its immune escape. (1) Macrophages are first recruited in tumor under the action of chemokines secreted by tumor cells. Some factors such as retinoic acid (113) and IL-6 (114) favor monocytes differentiation toward macrophages instead of dendritic cells. (2) Macrophages become TAMs with immunosuppressive activity, in particular due to sphingosine 1 phosphatase (S1P) released by dying tumor cells. (3) TAMs support local immunosuppression by: secreting immunosuppressive cytokines, inhibiting effector T-cells (115) and NK cells (116), recruiting Tregs though CCL22-CCR4 axis or MDSC through CCL2-CCR2. (4) Under hypoxia, macrophages produce various cytokines, including CCL-18 (117) triggered by tumor cells at the tumor invasive front, and proteases that induce EMT in tumor cells and favor their invasion and migration. Additional paracrine loops between tumor cells and TAMs, as described for EGF and CSF-1, amplify TAM-dependent cancer cell motility (94, 118). (5) Finally, TAMs contribute to anticancer treatment resistance by secreting factors protecting tumor cells from death.

Figure 4

SPMs as anticancer agents to resolve cancer-associated inflammation. Various extrinsic factors such as surgery and anticancer treatments as well as intrinsic hypoxia contribute to local inflammation within tumors. TAMs largely contribute to fuel tumor progression by various functions described in Figure 3 . Use of SPM would resolve cancer-associated inflammation by repolarizing TAMs toward a pro-resolving phenotype with increased efferocytosis capabilities. As a result, SPMs could induce tumor regression and prevent further metastasis establishment.