Abstract
Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients. At baseline, patient NK cells, particularly those isolated from high-risk patients with no measurable disease, showed altered distribution of CD56dim CD16+ and CD56dim CD16− NK cell subsets, as well as elevated serum levels of immune suppressive MICA, TN5E/CD73 and tactile/CD96, and perforin. Surprisingly, patient NK cells displayed a higher level of activation than those from healthy donors as measured by elevated CD69, NKp44 and CCR7 levels, and enhanced K562 killing. Elevated cytolytic ability strongly correlated with increased representation of CD56dim CD16+ NK cells and amplified CD69 expression on CD56dim CD16+ NK cells. While intradermal DC immunizations did not significantly impact circulatory NK cell activation and distribution profiles, subsequent HDI injections enhanced CD56bright CD16− NK cell numbers when compared to patients that did not receive HDI. Phenotypic analysis of tumor-infiltrating NK cells showed that CD56dim CD16− NK cells are the dominant subset in melanoma tumors. NanoString transcriptomic analysis of melanomas resected at baseline indicated that there was a trend of increased CD56dim NK cell gene signature expression in patients with better clinical response. These data indicate that melanoma patient blood NK cells display elevated activation levels, that intra-dermal DC immunizations did not effectively promote systemic NK cell responses, that systemic HDI administration can modulate NK cell subset distributions and suggest that CD56dim CD16− NK cells are a unique non-cytolytic subset in melanoma patients that may associate with better patient outcome.
Highlights
Malignant melanoma is the most lethal cutaneous cancer that causes the majority of skin cancer-related deaths (80%)
We examined the impact of intradermal AdV.dendritic cell (DC) ± systemic HDI administration on peripheral blood Natural Killer (NK) cell profiles in melanoma patients
healthy donor (HD) and melanoma patient sera were tested for immunosuppressive factors MICA, NT5E/CD73 and tactile/CD96, as well as perforin, which is released by cytotoxic NK and T cells and is a surrogate biomarker for in vivo cytolytic activity of these effectors [39]
Summary
Malignant melanoma is the most lethal cutaneous cancer that causes the majority of skin cancer-related deaths (80%). Therapies targeting mitogen-activated protein kinase (MAPK) signaling pathway in lesions that harbor mutated BRAF kinase and negative regulatory checkpoint molecules of the immune system [cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1)] became standards of care for metastatic melanoma [1,2,3] Clinical benefit of these therapies has been limited to a subset of patients, stressing the need for novel therapeutic modalities to treat melanoma. We have shown that combination of IFNα with AdV.DC further enhances NK cell activation and cytotoxicity in vitro [11] Based on these data, we examined the impact of intradermal AdV.DC ± systemic HDI administration on peripheral blood NK cell profiles in melanoma patients. We characterized differences in immunosuppressive serum factors, NK cell cytotoxicity, phenotype, and subpopulation distribution between patients with and without measurable disease and healthy donor controls in blood, and profiled subpopulation distributions of tumor-infiltrating NK cells (TINKs)
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