Manipulating macrophages to boost the anti-tumour function of natural killer cells

Abstract

Macrophages are innate immune cells that are abundant in the tumour microenvironment and display a range of phenotypes, ranging from anti-tumour (M1-like) to pro-tumour (M2-like). Natural killer (NK) cells are also innate immune cells and have potent anti-tumour functions including the direct lysis of target tumour cells and antibody-dependent cell-mediated cytotoxicity. Their function is governed by germline-encoded receptors, including killer cell immunoglobulin-like receptors (KIRs), one of which, KIR2DS2, is associated with beneficial cancer outcomes and the recognition of many solid tumours. Despite increasing interest in cell-communication, how distinct macrophage subsets influence NK cell activation, particularly via antigen presentation, remains poorly understood.

This thesis investigates how peptide-presenting macrophages modulate NK cell function, with a focus on KIR2DS2-activating peptides. Flow cytometry firstly revealed that M1-like macrophages enhance the activation of resting NK cells, whereas M2-like macrophages suppress it. In contrast, in shorter co-cultures, single-cell RNA sequencing demonstrated that M2-like macrophages can upregulate NK cell genes associated with activation, highlighting a more nuanced and temporally dynamic interaction.

Exogenous loading of M2-like macrophages with KIR2DS2-activating peptides overcame their suppressive effects after 24 hours. However, 12-hour sequencing of the co-cultures indicated that although peptide exposure increased NK cell proliferative gene signatures, it also induced features of dysfunction. Cytotoxicity assays further demonstrated that peptide-presenting macrophages prime NK cells for enhanced, target-specific killing. The dual stimulation, through peptide-loaded macrophages and peptide-expressing targets, may overcome the dysfunction revealed by sequencing.

Collectively, these findings reveal uncharacterised antigen-presentation-dependent crosstalk between macrophages and NK cells. By demonstrating that the immunosuppressive nature of M2-like macrophages can be reversed with KIR2DS2-activating peptides, thereby priming NK cells for target-specific cytotoxicity, this work identifies a pathway that could be harnessed to enhance NK cell-based cancer therapies. These results also highlight the therapeutic potential of targeting macrophage-NK cell signalling to optimise NK cell function.

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Identifiers

ORCID for Salim Khakoo: orcid.org/0000-0002-4057-9091

ORCID for Tilman Sanchez-Elsner: orcid.org/0000-0003-1915-2410

ORCID for Andres Vallejo Pulido: orcid.org/0000-0002-4688-0598

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