A core of kinase-regulated interactomes defines the neoplastic MDSC lineage.

Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics.

Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis.

Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied.

Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in tumor-bearing subjects and which strongly inhibit anti-cancer immune responses. To study the biology of MDSC in colorectal cancer (CRC), we cultured bone marrow cells in conditioned medium from CT26 cells, which are genetically modified to secrete high levels of granulocyte-macrophage colony-stimulating factor. This resulted in the generation of high numbers of CD11b(+) Ly6G(+) granulocytic and CD11b(+) Ly6C(+) monocytic MDSC, which closely resemble those found within the tumor but not the spleen of CT26 tumor-bearing mice.

Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity.

It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ², showed therapeutic potential.

A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice.

Myeloid-derived suppressor cells (MDSCs) exhibit potent immunosuppressive activities in cancer. MDSCs infiltrate tumors and strongly inhibit cancer-specific cytotoxic T cells. Their mechanism of differentiation and identification of MDSC-specific therapeutic targets are major areas of interest.

Anti-melanoma vaccines engineered to simultaneously modulate cytokine priming and silence PD-L1 characterized using myeloid-derived suppressor cells as a readout of therapeutic efficacy.

Efficacious antitumor vaccines strongly stimulate cancer-specific effector T cells and counteract the activity of tumor-infiltrating immunosuppressive cells. We hypothesised that combining cytokine expression with silencing programmed cell death ligand 1 (PD-L1) could potentiate anticancer immune responses of lentivector vaccines. Thus, we engineered a collection of lentivectors that simultaneously co-expressed an antigen, a PD-L1-silencing shRNA, and various T cell-polarising cytokines, including interferon γ (IFNγ), transforming growth factor β (TGFβ) or interleukins (IL12, IL15, IL23, IL17A, IL6, IL10, IL4).

Assessing T-cell responses in anticancer immunotherapy: Dendritic cells or myeloid-derived suppressor cells?

Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies.

Lentiviral vectors for cancer immunotherapy and clinical applications.

The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer.

Immune modulation by genetic modification of dendritic cells with lentiviral vectors.

Our work over the past eight years has focused on the use of HIV-1 lentiviral vectors (lentivectors) for the genetic modification of dendritic cells (DCs) to control their functions in immune modulation. DCs are key professional antigen presenting cells which regulate the activity of most effector immune cells, including T, B and NK cells. Their genetic modification provides the means for the development of targeted therapies towards cancer and autoimmune disease.

Retroviral and lentiviral vectors for the induction of immunological tolerance.

Retroviral and lentiviral vectors have proven to be particularly efficient systems to deliver genes of interest into target cells, either in vivo or in cell cultures. They have been used for some time for gene therapy and the development of gene vaccines. Recently retroviral and lentiviral vectors have been used to generate tolerogenic dendritic cells, key professional antigen presenting cells that regulate immune responses.

PD-L1/PD-1 Co-Stimulation, a Brake for T cell Activation and a T cell Differentiation Signal.

For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach.

MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY.

One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens.