Targeting natural killer cell receptors and their ligands for improved antibody-dependent cellular cytotoxicity

Abstract

Natural killer (NK) cells are cytotoxic cells of the innate immune system and are tightly regulated by a diverse range of activating and inhibitory receptors. NK cells have an important role in both directly lysing tumour cells and in regulating the wider immune response. These effector functions can be harnessed for the treatment of cancer. For example, via expression of CD16, NK cells contribute to the efficacy of therapeutic antibodies and engager molecules that trigger antibody-dependent cellular cytotoxicity (ADCC).

Immunogenetic analyses have found an association between the NK cell activating receptor KIR2DS2 and superior outcomes in cancer patients. In addition, NKG2A is upregulated on the surface of NK cells following ex vivo expansion required for adoptive transfer therapy and inhibits NK cell effector function upon ligation with its ligand, HLA-E. This project aims to investigate the potential of targeting these regulatory receptors for improving ADCC.

Using ex vivo cellular assays and a specialised flow cytometry panel, KIR2DS2high NK cells from the peripheral blood of healthy donors and patients with chronic lymphocytic leukaemia or hepatocellular carcinoma showed enhanced ADCC in the presence of tumour-targeting antibodies. However, the observed enhanced ADCC was lost following cytokine-based ex vivo expansion.

In addition, the lymph node microenvironmental support signals CD40L and IL-4 inhibited NK cell-mediated ADCC of malignant B cells and healthy B cells with anti-CD20 antibodies via the HLA-E:NKG2A axis. Interruption of this axis with antibodies targeting NKG2A enhanced NK cell-mediated ADCC in vitro and improved anti-CD20 therapy in an in vivo murine model of B cell lymphoma. Stimulation of NK cells via CD16 ligation also led to the upregulation of HLA-E expression on target cells through IFNγ secretion, further inhibiting ADCC.

Overall, these data indicate that KIR2DS2 may be a viable target for enhancing ADCC in patients, although is likely not advantageous in the context of adoptive transfer therapy. Meanwhile, blockade of the HLA-E:NKG2A axis may represent an effective strategy for overcoming resistance to ADCC induced by anti-CD20 antibodies within the lymph nodes and inflammatory microenvironments.

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Identifiers

ORCID for Lara Victoria Graham: orcid.org/0009-0006-5420-9020

ORCID for Matthew Blunt: orcid.org/0000-0003-1099-3985

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

ORCID for Mark Cragg: orcid.org/0000-0003-2077-089X

ORCID for Francesco Forconi: orcid.org/0000-0002-2211-1831

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