In their work published in Oncoimmunology, Raghd Al Olabi and Dr Mir Munir Rahim elucidate the role of the inhibitory NKR-P1B receptor interaction with C-type lectin-related protein-b (Clr-b) ligand in Natural Killer (NK) cell-mediated mammary tumour immunosurveillance in MMTV-PyVT mice. 

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NK cells are well known for the role they play in anti-cancer immune responses. NK cell functions are modulated by a plethora of activating and inhibitory cell surface receptors interacting with ligands expressed on the surface of target cells. NKR-P1B is a type of inhibitory receptor that recognises the Clr-b inhibitory ligand on the surface of target cells. Downregulation of inhibitory ligands, like Clr-b, on tumour cells can trigger NK cell activation in a process called the 'missing-self' response.

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Given the role of NKR-P1B:Clr-b interactions in cancer immune evasion, Al Olabi et al. studied the role of this interaction in mammary tumour immunosurveillance using MMTV-PyVT mice bred on NKR-P1B deficient (Nkrp1b-/-) background. MMTV-PyVT wild-type (WT) mice remained tumour-free for a significantly longer period than the NKR-P1B-deficient mice, which may be due impaired NK cell-mediated missing-self response against Clr-b negative target cells in NKR-P1B-deficient mice. They also observed an increased frequency of EOMES- CD49a+ tumour-infiltrating NK cells in NKR-P1B deficient mice compared to the WT mice. Ex vivo analysis of EOMES- CD49a+ tumour-infiltrating NK cells demonstrated increased granzyme B expression, indicating an activated phenotype, but showed reduced expression of Ki67 in larger mammary tumours, indicating reduced proliferative capacity. Furthermore, EOMES- CD49a+ tumour-infiltrating NK cells showed upregulation of immune exhaustion markers, such as LAG-3 and PD-1, while exhibiting significant loss of markers associated with NK cell function, maturation, and homeostasis. Thus, the EOMES- tumour-infiltrating NK cells were associated with a dysfunctional state within NKR-P1B deficient MMTV-PyVT mice compared to WT mice.

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Ultimately, Al Olabi et al revealed NKR-P1B:Clr-b interactions regulate anti-cancer responses and maintaining functional homeostasis in tumour-infiltrating NK cells. Further research investigating the mechanisms by which NK cell function is regulated in cancer can help realize the full potential of NK cells in cancer immunotherapy.