Thaïs Baert

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called “damage-associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

ABSTRACT Neoplastic cells can escape immune control leading to cancer growth. Regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) are crucial in immune escape. TAM are divided based on their immune profile, M1 are immunostimulatory while M2 are immunosuppressive. Research so far has mainly focused on the intratumoral behavior of these cells. This study, on the other hand, explored the systemic changes of the key metabolites [IL-4 (interleukin), IL-13, arginase, IL-10, VEGF-A (vascular endothelial growth factor), CCL-2 (chemokine (C-C) motif ligand 2) and TGF-β (transforming growth factor)] linked to Treg, MDSC and TAM during the course of the disease in ovarian and fallopian tube cancer patients. Serum samples were therefore analyzed at diagnosis, after (interval)-debulking surgery and after chemotherapy (paclitaxel–carboplatin). We also determined galectin-1 (gal-1), involved in angiogenesis and tumor-mediated immune evasion. We found significantly lower levels of IL-10, VEGF-A, TGF-β and arginase and higher levels of gal-1 after chemotherapy compared to diagnosis. After debulking surgery, a decrease in IL-10 was significant. Gal-1 and CCL-2 appeared independent prognostic factors for progression-free and overall survival (OS) (multivariate analysis). These results will help us in the decision making of future therapies in order to further modulate the immune system in a positive way.

The dark side of ID8-Luc2: pitfalls for luciferase tagged murine models for ovarian cancer

Reliable mouse models are key in the discovery and development of novel anticancer treatments. Non-invasive monitoring techniques such as bioluminescence imaging (BLI) are useful tools to determine tumor engraftment and evaluate tumor growth. However, the development of ascites in ovarian cancer mouse models leads to possible difficulties. Ascites can interfere with the set-up of correct end points and can interfere with the evaluation of tumor volume using BLI. We provide optimized euthanasia criteria and in vivo data underlining the pitfalls of BLI.

Ovarian cancer and the immune system

Short communication in response to the review of Turner et al. entitled “Ovarian cancer and the immune system - the role of targeted therapies” published in Gynecological Oncology. We believe systemic immune parameters might be a good alternative to tumor biopsy to gain insight in the immunological background of ovarian cancer.

Influence of CA125, platelet count and neutrophil to lymphocyte ratio on the immune system of ovarian cancer patients

OBJECTIVE The effect of CA125, neutrophil to lymphocyte ratio (NLR) and thrombocytosis on survival has been studied in ovarian cancer. This study explores the link between these variables and serum markers of ovarian cancer patients, such as signaling proteins and cytokines. METHODS Serum samples of 39 patients with high-grade serous ovarian cancer (HGSOC) were collected at diagnosis and were retrospectively analysed for clinical characteristics, clinical parameters (NLR, CA125, platelet count) and immune profile [IL-4 (interleukin), IL-10, IL-13, IL-17, transforming growth factor-β, Arginase-1, Interferon gamma), vascular endothelial growth factor (VEGF), galectin-1 and chemokine (C-C) motif ligand 2. RESULTS CA125 correlates negatively with VEGF (p = 0.02) and if CA125 rises above 500 kU/L, IL-10 is significantly increased (p = 0.01). NLR > 6 (p < 0.01) was significantly correlated with decreased overall survival. Thrombocytosis was significantly correlated with IL-10 (p < 0.01) and a platelet count > 400 × 109/l led to an improvement in progression free survival (p < 0.01). CONCLUSIONS A correlation, at the time of diagnosis, of HGSOC between CA125, NLR and thrombocytes and an immunosuppressive cytokine-profile in serum is shown, and correlates with survival.

Low-grade Serous Ovarian Carcinoma

In the early 2000s a two-tier grading system was introduced for serous ovarian cancer. Since then, we have increasingly come to accept that low-grade serous ovarian carcinoma (LGSOC) is a separate entity with a unique mutational landscape and clinical behaviour. As less than 10% of serous carcinomas of the ovary are low-grade, they are present in only a small number of patients in clinical trials for ovarian cancer. Therefore the current treatment of LGSOC is based on smaller trials, retrospective series, and subgroup analysis of large clinical trials on ovarian cancer. Surgery plays a major role in the treatment of patients with LGSOC. In the systemic treatment of LGSOC, hormonal treatment and targeted therapies seem to play an important role.

Orientation of Preclinical Research in Ovarian Cancer

Objectives A large variety of mouse models for cancer exist, also in the field of ovarian cancer. Each model possesses different features, which makes it difficult to interpret their translational value. This review provides an overview of the available ovarian cancer mouse models and their possible use in search for new treatments. Methods This was a PubMed search of available literature on genetically engineered mouse models, xenografts, transplantable models, and immunocompetent mouse models in ovarian cancer, with a specific focus on clinically relevant features of the described models. Results/Conclusions Several preclinical models are available for ovarian cancer. Based on their properties, a model should be carefully selected as a function of the experimental setup to achieve clinically relevant results.