The CCAAT/Enhancer-Binding Protein Family: Its Roles in MDSC Expansion and Function.

Immunosuppressive cells have been highlighted in research due to their roles in tumor progression and treatment failure. Myeloid-derived suppressor cells (MDSCs) are among the major immunosuppressive cell populations in the tumor microenvironment, and transcription factors (TFs) are likely involved in MDSC expansion and activation. As key regulatory TFs, members of the CCAAT/enhancer-binding protein (C/EBP) family possibly modulate many biological processes, including cell growth, differentiation, metabolism, and death. Current evidence suggests that C/EBPs maintain critical regulation of MDSCs and are involved in the differentiation and function of MDSCs within the tumor microenvironment. To better understand the MDSC-associated transcriptional network and identify new therapy targets, we herein review recent findings about the C/EBP family regarding their participation in the expansion and function of MDSCs.

Neutrophil Maturity in Cancer.

Neutrophils are implicated in almost every stage of oncogenesis and paradoxically display anti- and pro-tumor properties. Accumulating evidence indicates that neutrophils display diversity in their phenotype resulting from functional plasticity and/or changes to granulopoiesis. In cancer, neutrophils at a range of maturation stages can be identified in the blood and tissues (i.e., outside of their developmental niche). The functional capacity of neutrophils at different states of maturation is poorly understood resulting from challenges in their isolation, identification, and investigation. Thus, the impact of neutrophil maturity on cancer progression and therapy remains enigmatic. In this review, we discuss the identification, prevalence, and function of immature and mature neutrophils in cancer and the potential impact of this on tumor progression and cancer therapy.

NF-Y and the immune response: Dissecting the complex regulation of MHC genes.

Nuclear Factor Y (NF-Y) was first described as one of the CCAAT binding factors. Although CCAAT motifs were found to be present in various genes, NF-Y attracted a lot of interest early on, due to its role in Major Histocompatibility Complex (MHC) gene regulation. MHC genes are crucial in immune response and show peculiar expression patterns. Among other conserved elements on MHC promoters, an NF-Y binding CCAAT box was found to contribute to MHC transcriptional regulation. NF-Y along with other DNA binding factors assembles in a stereospecific manner to form a multiprotein scaffold, the MHC enhanceosome, which is necessary but not sufficient to drive transcription. Transcriptional activation is achieved by the recruitment of yet another factor, the class II transcriptional activator (CIITA). In this review, we briefly discuss basic findings on MHCII transcription regulation and we highlight NF-Y different modes of function in MHCII gene activation. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.

A point mutation in the NFYC gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human squamous cell lung carcinoma.

We have identified an antigen recognized by cytolytic T lymphocytes (CTL) on the autologous tumor cells of a nonsmall cell lung cancer patient. The antigenic peptide, presented by HLA-B*5201 molecules, was encoded by a mutated sequence in the gene coding for the C subunit of transcription factor NF-Y. The mutation was present in the tumor sample from which the cell line was derived, and appeared to be unique to the tumor of this patient. In a lymph node draining the tumor, precursors of CTL recognizing the autologous tumor cells were detected at a frequency of about 1/30,000 of the CD8 cells, and 85% of them recognized the mutated NF-YC peptide, suggesting that the patient mounted a T cell response against this antigen. These results strengthened the notion that unique tumor-specific antigens are highly represented not only in melanoma but also in other types of tumors, like nonsmall cell lung cancer.