Dendritic cells (DC) are specialized immune cells that play a critical role in promoting an immune response against Ags, which can include foreign pathogenic Ags and self-tumor Ags. DC are capable of boosting a memory T cell response but most importantly they are effective initiators of naive T cell responses. Many years of studies have focused on the use of DC vaccines against cancer to initiate and shape an antitumor-specific immune response and/or boost existing spontaneous antitumor T cell responses. In this study we give a brief overview of DC biology, function, and cellular subsets, and review the current status of the field of DC as cancer vaccines.
Head and neck squamous cell carcinoma (HNSCC) is characterized by complex relations between stromal, epithelial, and immune cells within the tumor microenvironment (TME). To enable the development of more efficacious therapies, we aim to study the heterogeneity, signatures of unique cell populations, and cell-cell interactions of non-immune and immune cell populations in 6 human papillomavirus (HPV)+ and 12 HPV– HNSCC patient tumor and matched peripheral blood specimens using single-cell RNA sequencing. Using this dataset of 134,606 cells, we show cell type-specific signatures associated with inflammation and HPV status, describe the negative prognostic value of fibroblasts with elastic differentiation specifically in the HPV+ TME, predict therapeutically targetable checkpoint receptor-ligand interactions, and show that tumor-associated macrophages are dominant contributors of PD-L1 and other immune checkpoint ligands in the TME. We present a comprehensive single-cell view of cell-intrinsic mechanisms and cell-cell communication shaping the HNSCC microenvironment.
Differentiation of B cells into antibody secreting cells induces changes in gene transcription, Igh RNA processing, the unfolded protein response, and cell architecture. The transcription elongation factor ELL2 (eleven nineteen lysine-rich leukemia gene) stimulates the processing of the secreted form of the Igh mRNA from the heavy chain gene. Mice (mus musculus) with the ELL2 gene floxed in either exon 1 or exon 3 were constructed and crossed to CD19 driven cre/ CD19+. The B-cell specific ELL2 conditional knockouts (ell2loxp/loxp CD19cre/+) exhibit curtailed humoral responses both in NP-ficoll and NP-KLH immunized animals; recall responses were also diminished. The number of immature and recirculating B cells in the bone marrow is increased in the conditional knockouts while plasma cells in spleen are reduced relative to control animals. There are fewer IgG1 antibody producing cells in the bone marrow of conditional knockouts. LPS ex vivo stimulated B220loCD138+ cells from ELL2 deficient mouse spleens are 4-fold less abundant than from control splenic B-cells, have a paucity of secreted Igh, and distended, abnormal appearing ER. IRE1alpha is efficiently phosphorylated but the amounts of Ig kappa, ATF6, BiP, Cyclin B2, OcaB (BOB1, Pou2af1), and XBP1 mRNAs, unspliced and spliced, are severely reduced in ELL2 deficient cells. ELL2 enhances the expression of BCMA, important for long term survival. Transcription yields from the cyclin B2 and the canonical UPR promoter elements are up-regulated by ELL2 cDNA. Thus ELL2 is important for many aspects of antibody secretion, XBP1 expression, and the unfolded protein response.
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.
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