Tumor-Associated Macrophages: From Mechanisms to Therapy

Abstract

The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate these macrophages generally play a pro-tumoral role. In the primary tumor, macrophage can stimulate angiogenesis and enhance tumor cell invasion, motility and intravasation. During metastasis, macrophages prime the pre-metastatic site and promote tumor cell extravasation, survival and persistent growth. Macrophages are also immunosuppressive preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immuno-therapy. Therapeutic success in targeting these pro-tumoral roles in pre-clinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment.

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…Newly recruited monocytes in the tumor are in contact with ATPderived nucleotides which may participate to the acquisition of an IL-10 high IL-12 low immunosuppressive phenotype. 10,60 As CD39 is located upstream the ATP metabolism, we hypothesized that manipulating the ATP/AMP ratio may modulate the immunosuppressive properties of M-CSF-macrophages. Accordingly, we observed that CD39 inhibition or adenosine depletion enhanced the capacity of activated TAM and M-CSF-macrophages to produce IL-1b and reduced their capacity to produce IL-10.…”

“…IL-10, VEGF, MMPs, IDO). 60 For this concern, to identify strategies that may inhibit their recruitment, block their generation, reverse their trophic and immunosuppressive roles or interfere with their survival may represent new therapeutic opportunities. 10 As a matter of fact, our study identifying the role of membrane CD39 in the acquisition and maintenance of an immunosuppressive phenotype by M-CSF-macrophages and TAM, could define ATP metabolism and IL-27 as privileged targets.…”

Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis

“…In colorectal carcinoma, TAMs have been shown to release growth factors, matrix-remodeling enzymes and promote vascularization. [7][8][9] The vascularization is often strictly dependent on macrophages and is fundamental for the tumor growth, invasion and metastatization. New vessels provide oxygen, nutrients and growth factors and allow cancer cells to extravasate and disseminate.…”

Single‐cell technologies to study the immune system

“…tumour‐associated macrophages)? Tumour‐associated macrophages are structurally plastic and heterogeneous, and functionally crucial for determining the fate of a tumour 52. These cells are widely accepted to be a cause of anti‐tumour immune suppression.…”