Two Sources and Heterogeneity of TAMs

TAMs, as the most abundant innate immune population in the tumor microenvironment (TME), account for approximately 50% of local hematopoietic cells. They share the same heterogeneity from anti-tumor to pro-tumor and differentiable plasticity.

Two Sources of TAMs

It is currently believed that TAM sources include two main types:

• Monocytes produced by bone marrow (BM) myeloid progenitor cells: these include classical Ly6C+ monocytes and non-classical Ly6C- patrolling monocytes. These monocytes leave the circulation and further differentiate into macrophages in tissues.
• Early embryonic origin: yolk sac or fetal liver. Also differentiated in tissues, their differentiated macrophages become tissue-resident macrophages (TRMs), which are present in various healthy tissues and are involved in cancer growth and metastasis.

Differentiation and proliferation of both are regulated by CSF1R and its ligands IL-34 and CSF1.

BM-derived Monocytes

Driven by persistent, low-level stimulatory signals mediated by tumor-derived growth factors, cytokines, and DAMPs, the normal differentiation process of myeloid progenitor cells becomes restricted, resulting in the accumulation of myeloid-derived suppressor cells (MDSCs). This is a class of myeloid cells with immunosuppressive and tumor-promoting effects.

The characterization of MDSCs in both mice and humans mainly contains two subgroups, mononuclear MDSCs and multinuclear MDSCs.

• Mononuclear MDSCs are dependent on cytokines and chemokines produced early in the tumor such as GM-CSF, IL-1β, SDF1α, VEGF, CSF1, and CCL2 thereby being recruited into the TME at the primary tumor site.
• IL-1β, SDF1α, and VEGF specifically activate G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and TLR/IL-1R, thereby mediating the production of TAMs.

Tissue-resident Macrophages

TRMs are affected by tumor-produced soluble factors and other TME damage. They undergo early inflammatory changes, assist in the recruitment of BM-derived monocytes, and promote the generation of TAMs.

The extent to which TRMs are involved in progression in different tumors is somewhat organ-specific.

• Breast cancer model: the number of TRMs decreases over time, while the number of TAMs produced by BM-derived monocytes increases simultaneously.
• Pancreatic cancer model: TRMs proliferate during tumor progression and acquire a transcriptional profile that favors pancreatic cancer fibrosis. Reduction of BM-derived TAMs did not affect this process but could be reversed by disruption of TRMs.
• Lung cancer model: macrophages from both sources promote tumor growth and progression. Alveolar macrophage depletion reverses immunosuppression, enhances local Th1 cell responses, and reduces tumor burden at metastatic sites.
• Primary and metastatic brain cancer: glioblastoma consists of TRMs, microglia, and BM-derived TAMs, the latter two of which are definitively located in heterogeneous cells. Metastatic brain tumors consist mainly of BM-derived TAMs. Glioblastoma TMEs exert different patterns of gene regulation on microglia and BM-derived macrophages.

Heterogeneity of Differentiated TAMs

Differential tumor-promoting capacity may exist between subpopulations of differentiated TAMs that are subject to different regulatory effects.

• A subpopulation of TAMs expressing the angiopoietin receptor Tie2 accumulates in the perivascular region for angiogenesis, tumor proliferation, and recurrence after chemotherapy.
• Transcription factor IRF8 regulates a subpopulation of TAMs to prevent distal tumor metastasis.
• Up-regulation of REDD1 allows TAMs in a hypoxic environment to block glycolysis and promote abnormal angiogenesis and tumor metastasis.

Both bone marrow-derived monocytes and tissue-resident macrophages contribute to TAM biology, and perhaps both could be targeted as strategies for reprogramming TAM into antitumor effectors.

Reference

1. Christofides, Anthos, et al. "The complex role of tumor-infiltrating macrophages." Nature immunology 23.8 (2022): 1148-1156.