NK Cells in the Lymph Nodes and Their Role in Anti-Tumour Immunity

Abstract

The lymph nodes are vital to enable adaptive immune responses to infection. Natural killer (NK) cells are cytotoxic lymphocytes that directly kill cancer cells and modulate the activation of other immune cells during anti-tumour immune response. NK cells in the lymph nodes are involved in the regulation of T-cell and B-cell populations and the clearance of viral infections. In solid tumours, lymph nodes are a frequent site of metastasis and immune cell priming, whilst in haematological malignancies, tumour cells can proliferate in the lymph nodes. Thus, lymph nodes are an important site in anti-tumour immunity and therapy resistance. It is therefore crucial to identify strategies to increase recruitment and overcome suppression of NK cells in the lymph node microenvironment to improve tumour clearance. In this review, we summarise the literature interrogating NK cell phenotype and function in the lymph nodes in the context of infection and cancer and evaluate both current and potential strategies to mobilise and activate NK cells within the lymph nodes of cancer patients.

Keywords: cancer; immunotherapy; lymph nodes; natural killer (NK) cells.

Figure 1

Distribution of NK cells in the lymph nodes. NK cells have been reported in the lymph node sinuses and paracortex of humans and the medulla, paracrotical and cortical areas of the lymph nodes in mice. Created with Biorender.com.

Figure 2

Potential strategies for mobilising and activating NK cells in the lymph nodes of cancer patients. Increasing expression of lymph node-homing receptors via nicotinamide and IL-15 culture or mRNA transfection methods increases lymph node homing of adoptively allogeneic NK cells and could be applied to CAR-NK therapy. Upregulation of HLA-E on malignant B cells by lymph node-associated signals can reduce NK cell function via NKG2A; therefore, blockade of either HLA-E or NKG2A could increase NK cell activation in the lymph nodes. Lymph node-targeting liposomes can increase NK cell recruitment and activation in the lymph nodes. Dipeptidyl peptidase inhibitors prevent cleavage and inactivation of lymph node-recruiting chemokines CXCL9/10, which may be beneficial for increasing lymph node homing. Created with Biorender.com.