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For the very first time, scientists have captured macrophage immune cells engulfing live melanoma cells, offering a glimpse into this elusive process that could inspire new treatments for the aggressive skin cancer.
Using intravital two-photon microscopy, researchers from the Garvan Institute of Medical Research and UNSW Sydney (both Australia) have observed the never-before-seen interaction between immune housekeeping proteins and cancer cells in real time, identifying potential targets for future melanoma treatments.
Macrophages in the skin are integral to a number of essential cellular processes, including tissue homeostasis, wound healing, pathogen surveillance and allergic inflammation. The immune cells are also known to be involved in skin cancer, interacting with cancer cells in the tumor immune microenvironment (TIME), extra-TIME and tumor-draining lymph nodes; however, their exact role in anti-tumor immunity is yet to be revealed.
In an attempt to untangle this, the team targeted a subpopulation of macrophages expressing the protein CD169. CD169+ macrophages play a part in promoting adaptive humoral immunity by presenting captured antigens to B cells and T cells. Clinical research has identified that a higher density of CD169+ macrophages in the tumor-draining lymph nodes is associated with a better prognosis in cancer patients, while animal studies have shown the immune cells can suppress melanoma growth.
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Building on this work, the researchers employed intravital microscopy to image CD169+ macrophages that reside near blood vessels in the hypodermis, the innermost layer of skin, witnessing the engulfment and ingestion of live tumor cells in mouse models.
Intravital microscopy and immunofluorescence microscopy on mice injected with B16-F10 melanoma cells expressing the red fluorescent protein mCherry demonstrated that CD169+ macrophages phagocytose live tumor cells to directly control the growth of B16-F10 melanomas in the skin. You can see this in the video embedded below.
Macrophages directly interact with melanoma cells. (A–D) Time-lapse intravital imaging of B16-F10 melanoma on day 1, with treatment of isotype mAb (A and B) and anti-CSF1R mAb (C and D). B16-F10-mCherry (magenta), SHG (blue), LYZM-Kikume-Mϕ (green), and LYZM-Kikume-neutrophil/monocytes (orange). Credit: Kieth YH et al. Video and legend reshared from the original article under the terms of the CC-BY 4.0 licence. No changes were made to the video or legend.
The team also analyzed skin biopsies from human patients via immunostaining, finding that CD169+ macrophages are enriched in the hypodermis in healthy and melanoma tissues.
To investigate the mechanism of tumor suppression, the team used flow cytometry on tumor-infiltrating leukocytes, revealing that the macrophages control tumors independent of T and B cells. This was supported by studies involving CD169+ macrophage depletion in mice engineered to lack T and B cells, which resulted in unrestrained tumor growth.
The discovery that T and B cells are not involved is “unexpected, and genuinely exciting”, Tri Phan, senior author on the paper, emphasized, as these are “the immune players most commonly credited with fighting cancer.”
Together, the findings expand our understanding of mysterious macrophages and their role in immune control of cancer, while also pointing to a potential therapeutic target, particularly for immune ‘cold’ tumors, which don’t trigger a strong immune response.
“If we can harness this population of macrophages, we potentially have an immune army already in place, ready to be mobilized,” Phan continued.
“This is the first time anyone has captured a macrophage attacking and engulfing a live cancer cell in real time,” first author Yuki Keith added. “We always suspected macrophages were doing more than we gave them credit for – now we have the video footage to prove it. Studying this in a living system is crucial because it is more representative of what happens in real life, showing the complexity of the immune system and paving the way for the treatments of the future.”
The post Macrophage vs melanoma: immune cells attack live cancer cells in world-first footage appeared first on BioTechniques.
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