Memory-like Differentiation Enhances NK Cell Responses to Melanoma

Abstract

◥Purpose: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cellrefractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined.Experimental Design: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNg and kill melanoma targets in vitro and in vivo using a xenograft model.Results: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNg production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D-and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells.Conclusions: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

Back to the Future: Spatiotemporal Determinants of NK Cell Antitumor Function

“…MDSCs increased CD155 and CD112 expression in an ROS-dependent manner, and CD155-TIGIT engagement inhibited ERK and ZAP70 signaling in NK cells. These data appear to support studies in advanced melanoma suggesting that cytokine-induced memory-like NK cells can exhibit superior antitumor function ( 131 ). Additionally, TIGIT-blocking ICB may be a promising new avenue toward releasing MDSC inhibition of NK cells in the TME.…”

“…In human disease, examination of metastases and lymph nodes from patients with advanced melanoma revealed that infiltrating NK cells were predominantly immature and less cytotoxic CD56 bright CD16 - subsets, while mature cytolytic CD56 dim CD16 + tumor-infiltrating NK cells that were present expressed lower levels of granzyme B and perforin compared to NK cells in peripheral blood ( 131 ). This suggests that the TME can affect both maturation and effector function, though the discussion surrounding the origin of CD56 bright versus CD56 dim NK cells raises the question of whether these cells are developmentally arrested or represent differential immunosuppression of two distinct terminal NK cell types.…”

A Hot Topic: Cancer Immunotherapy and Natural Killer Cells

“…The logical next step, besides ameliorating and extending the efficiency in hematological malignancies, namely to test this treatment modality in solid tumors, was likewise addressed by the Fehniger group [ 64 ]. In this field, advanced melanoma is an example with a highly unmet clinical need.…”

“…When performing in vitro experiments and using the power of mass cytometry, the authors could show that the CIML NK cells had strong cytolytic activity and cytokine production towards allogeneic and autologous melanoma target cells, suggesting that this type of NK cell effectors can overcome the frequently observed dysfunction in melanoma patients. In a mouse xenograft model, it appeared that the CIML NK cells had a better efficiency than conventional NK lymphocytes against transplanted melanoma tumors [ 64 ].…”

“…Whereas initially, exhausted T cells were almost exclusively in the focus of checkpoint inhibition strategies, the same principle actually holds true for NK cells from individuals affected by cancer: these lymphocytes are phenotypically abnormal and functionally deficient [ 64 ], but it is possible to act on the checkpoints to restore the ability of fighting the tumor. The first monoclonal antibodies targeting NK cell IR and to be clinically tested were the anti-KIR2DL1, -KIR2DL2, and -KIR2DL3 molecule lirilumab, which blocks the inhibitory interaction of the KIR with HLA-C proteins [ 89 ], and the anti-NKG2A antibody monalizumab, interfering with the binding of the IR NKG2A, expressed by subsets of NK cells and CD8+ T lymphocytes, with its ligand HLA-E [ 90 , 91 ].…”