The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

Abstract

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.

The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy

“…These liposomes containing clodronate are endocytosed by phagocytes (like TAMs) and after degradation of the phospholipid bilayer, the clodronate is released in the cytoplasm of the cells and thereby causing TAM apoptosis 173 . However, this approach is not specific and very toxic due to its capacity of targeting the entire phagocyte compartment 104,173 …”

“…Several papers, including by our lab recently, have reviewed the effect of metabolic stress in TAMs and their pro-tumorigenic consequences. [104][105][106][107] Hence, we will not discuss this here further and instead request the readers to refer to these more comprehensive theses. Nevertheless, it is very well established that hypoxia contributes to the attraction and retention of TAMs in the tumor, wherein HIF activation and lactic acid contribute to the anti-inflammatory M2-like phenotype of TAMs, and increase their angiogenic functions, which promotes tumor growth and progression.…”

“…173 However, this approach is not specific and very toxic due to its capacity of targeting the entire phagocyte compartment. 104,173…”

“…CCR2 is expressed by TAMs, monocytes, DCs, endothelial cells, neutrophils, and lymphocytes 161 . Through blockade of the CCL2‐CCR2 axis, the recruitment of TAMs to the tumor site can be inhibited; however, initial clinical trials had a rather minor effect on tumor progression 104,162 . A human anti‐CCR2 antibody, Carlumab, alone and combined with chemotherapy only resulted in a temporary suppression of CCR2 in the serum and had no antitumoral effect 163 .…”

In vitro flow cytometry assay to assess primary human and mouse macrophage phagocytosis of live cells

“…While this assay gives a quantitative measure of tumor cell uptake by macrophages, it is not possible to distinguish whether the macrophages are engulfing live tumor cells or if they are taking up remnants from dead cells. 3 We used video microscopy to show that LCL and lymphotoxin-treated macrophages do engulf live tumor cells, 1 but this cannot be directly concluded from a flow-cytometry based phagocytosis assay. Therefore, it is important to keep the tumor cells healthy when plating onto macrophages and minimize the number of dead tumor cells present in the coculture.…”