Chemotherapy, lipid metabolism & tumoral immune response

Tumors are frequently characterized by the presence of an inflammatory environment and the presence of an immune cell infiltrate. Our research team focuses on the relationships between cancer cells, inflammation and CD4 T cell lymphocytes. We are also studying the impact of fatty acids and of chemotherapeutic treatments on immune and cancer cells. A better understanding of these mechanisms will ultimately result in improved therapeutic strategies against cancer.

Our research themes :

Team involved in this project :

  • Ghiringhelli François (PU-PH) Contact : fghiringhelli@cgfl.fr
  • Martin François (Pr Emerite)
  • Ladoire Sylvain (MCU-PH)
  • Mignot Grégoire (Post-doc)
  • Bruchard Mélanie (PhD)

It has been recently shown that the immune system can make a decisive contribution to the therapeutic efficacy of conventional anticancer immune therapies (chemotherapy and radiotherapy). Our goal is to design chemo-immunotherapeutic protocols tailored to every patient. For this, we will consider not only the disease but also the patients’ immune status and the anticancer agents they receive. Thus, we study the effects of classical chemotherapeutic drugs (taxanes, gemcitabine, oxaliplatin, cyclophosphamide, doxorubicin) on immune effectors and regulatory cells (such as regulatory T cells and myeloid-derived suppressor cells) present in the tumor microenvironment. Using this knowledge, we attempt to define the best associations of chemotherapies that drive immune activation. In addition, a translational research study is carried out in collaboration with the Centre Georges François Leclerc to evaluate the nature of the immunological infiltrates in breast cancer tumors treated with chemotherapy.

Team involved in this project :
  • Apetoh Lionel (CR1) Contact : lionel.apetoh@inserm.fr
  • Vegran Frédérique (Post-doc)
  • Dosset Magalie (Post-doc)
  • Berger Hélène (PhD)
  • Humblin Etienne (PhD)

Our group investigates the relationships between CD4 T lymphocytes and anticancer immune responses. Effector CD4 T cells were initially classified in 1986 by Mossman and Coffman into Th1 and Th2 cells.  Th1 cells limit infections caused by intracellular bacteria while parasitic infections favor Th2 cell expansion. In the setting of cancer immunity, Th1 cell polarization is associated with an effective anticancer immune response in contrast to Th2 cell immunity, which possibly contributes to tumor growth. Novel subsets of CD4 T lymphocytes have now been identified like Th17 cells (secreting IL-17) and Th9 cells (secreting IL-9). These cells are known to be highly proinflammatory in vivo. However, their putative contribution to tumor progression remains incompletely defined. Our group aims to determine the molecular mechanisms that can endow Th17 and Th9 cells with anticancer properties to contemplate the use of these cells in anticancer adoptive T cell therapy.

Team involved in this project :

  • Rébé Cédric (IB) Contact : crebe@cgfl.fr
  • Derangère Valentin (PhD)
  • Chevriaux Angélique (TR CGFL)

The inflammasome is an intracellular multi-protein complex which mostly allows the activation of caspase-1 and the maturation of pro-inflammatory cytokines such as Interleukin-1β. Different inflammasomes exist and are characterized by protein components, the most described being Nlrp3 inflammasome. This one can be activated by various stimuli such as pathogens and the molecules they produce, environmental damages or intracellular molecules.
Our objective is to understand the Nlrp3 inflammasome in a tumoral context. For this we study:


1- The molecular mechanisms involved in inflammasome formation and caspase-1 activation mediated by classic activators such as ATP, Alum, nigericin….
2- The role of apoptosis protein regulators in inflammasome formation and caspase-1 activation.
3- The molecular mechanisms involved in inflammasome formation and caspase-1 activation by new activators such as ligands of the nuclear receptor LXR (Liver X Receptor).

Lipid Metabolism and cancers :

Team involved in this project :

  • Delmas Dominique (MCU) Contact : ddelmas@u-bourgogne.fr
  • Cotte Alexia (PhD 1ère année)
  • Limagne Emeric (IE)
  • Scagliarini Alessandra (Post-doc)
  • ATER

The tumor cell has acquired various strategies to counteract the effects of anticancer drugs by using deregulation of mechanisms controlling life and physiological cell death. The therapeutic challenge is two-fold:
- Amplify pre-existing anti-tumor response (or induce)
- Act on the mechanisms preventing apoptosis of tumor cells and the accumulation of drugs in cells.

It is thus necessary to understand the interdependence of complex biological systems as the cell cycle, apoptosis, telomeres, angiogenesis, immune system and the tumor microenvironment. This tumor microenvironment plays a major role in drug resistance and in the selection of malignant and metastatic phenotypes, through hypoxia and acidification phenomena associated with tumor metabolism. An increasing number of clinical and biological arguments suggest that there is a control of the tumor development and growth by the metabolism of tumor cells. However, the relationship between the alteration of cellular lipid metabolism and tumor resistance is still poorly understood.

We have developed a cross-disciplinary research project at the Inserm Research Center U866 "Lipids, Nutrition, Cancers" aimed at assessing the impact of the complex lipids composition in tumor progression and in the chemotherapeutic treatment responses. This project would establish the relationship between the lipid metabolism disruption and the tumor resistance (Figure 1). Our team has developed a translational research program in partnership with the Division of Gastroenterology of the University Hospital of Dijon and the Anticancer Center GF Leclerc. This research reinforces the recent certification of the laboratory of excellence (Labex Lipstic) controlled by the Inserm Research Center where our team participates actively.
Ultimately, the identification of new markers in lipid metabolism will provide additional tools for imaging and clinical examination in the prognostic evaluation of digestive cancers. Moreover, the discovery of new targets in the lipid metabolism could contribute to the development of new therapeutic approaches aimed at increasing the sensitivity to anticancer drugs.

Contact : Dominique Delmas

Email : ddelmas@u-bourgogne.fr

 

Polyphenols – Health, Valuation by industrial transfert:

Team involved in this project :

  • Delmas Dominique (MCU)
  • Cotte Alexia (PhD)
  • Limagne Emeric (IE)
  • Scagliarini Alessandra (Post-doc)

Our team studied the chemopreventive and therapeutic potential of natural molecules in order to search new bioactive molecules able to prevent the onset of diseases (cancer, inflammation, auto-immune diseases), or to increase their sensitivity to conventional therapies. This increase in sensitivity is important because drug toxicity is often a factor limiting the use in clinic of these drugs. That’s why an increase in chemosensitivity should reduce therapeutic levels and improve survival rates.

Our research is mainly focused on polyphenols that appear to be good candidates in chemoprevention or in chemosensitization strategy. Indeed, we have shown that polyphenols, including resveratrol, are able to stop the proliferation of cancer cells through a disruption of the cell cycle which is blocked in the phase of DNA replication (S phase). This blockage results from a modulation of key cell cycle regulators such as cyclin-dependent kinases (Cdks) and cylins. A cell that is unable to divide, will undoubtedly evolve into a process of programmed cell death called apoptosis (Figure 2).

We have shown that resveratrol was able to induce cell death by apoptosis through the aggregation of death receptors into lipid microdomains, lipid rafts, of colon tumor cells. This clustering of death receptors is an essential step to sensitize tumor resistant cells to apoptosis-induced by the cytokine TRAIL.

In order to increase the efficiency of resveratrol, we synthesized (in partnership with organic chemistry laboratories) structural analogues of resveratrol that are able to block the cell cycle in S phase and to induce sensitization of cancer cells to anticancer agents such as 5 fluoro-uracil.

Our experience in the field of membrane dynamics and metabolism of xenobiotics, allowed us i) to identify the metabolites of resveratrol, sulfo and glucuronoresveratrol that present anticancer properties; ii ) to determine the mechanism of resveratrol uptake in tumor cells involving an endocytosis via lipid microdomains of the plasma membrane which control the biological effects of polyphenol; iii) to determine the biological effects of metabolites of resveratrol.

More recently, our team focused on the actions of polyphenols in the immune and inflammatory responses in various biological models.

In parallel, our team developed a valuation by industrial transfer, this axis of research aims at proposing to the industrialist our know-how and expertise in the field of natural molecules or extracts or synthetic molecules (Figure 2).
We were able to:
1°) Determine the health potential of these molecules or extracts;
2°) Study their molecular and cellular and mechanisms of action in vitro and in vivo;
3°) Supply a scientific support in the fields of immunology, inflammation and lipid metabolism.

The expertise and accompaniment of research projects with industry are achievable within the framework of R&D contracts subjected to research-credit taxes.

 

Contact : Dominique Delmas
Email : ddelmas@u-bourgogne.fr

Lipid metabolism, fatty acids, polyphenols and colorectal cancer:

Team involved in this project :

Fatty acids participate to the control of tumor growth. Among their functions, they are able to regulate both proliferation of cancer cells and inflammatory status of tumoral microenvironment. In this context, a therapeutic agent interfering with intrinsic proliferation capabilities of cancer cells and with pro-inflammatory signals would be more efficient for an anti-cancer action. In the tumoral environment, the regulation of Th17 lymphocyte differentiation would control the inflammatory status and cancer progression. The docosahexaenoic acid (DHA), an n-3 fatty acid, presents both functions: anti-inflammatory and anti-proliferative effects.
We developed strategies in order 1) to define the effect of DHA on differentiation of pro-inflammatory Th17 lymphocytes, 2) to determine the molecular mechanisms controlling the pro-apoptotic effects of DHA on colon cancer cells. We focused the study on the role of micro-RNAs in the DHA effects.
Moreover, reprogramming of metabolism such as monounsaturated fatty acid (MUFA) synthesis is an hallmark of cancer cells. Stearoyl-CoA desaturase 1 (Scd1) is the enzyme catalyzing the production of MUFA and its expression is increased in tumoral tissues. Activity of Scd1 is necessary to survival and proliferation of cancer cells (Minville-Walz M et al., 2010, PloS One). We are investigating the role of Scd1 in the mechanisms regulating the proliferation of cancer cells and the associated metabolic changes.

Team involved in this project :

Research topics: this group works since more than 15 years on basic, translational and clinical research in the field of surgical oncology. Our aim is to improve the use of chemotherapy drugs in surgical oncology for the treatment of locally advanced or metastatic neoplasms. For each topic we start with the in vitro experiments, then with the in vivo small models, then with the feasibility studies in large animals and finally in clinical trials. We have 3 main topics of research:

  1. New techniques of intracavitary chemotherapy (intraperitoneal and intrapleural chemotherapy). This group is well-known in the field of peritoneal carcinomatosis. In the field of  Heated Intraperitoneal Chemotherapy (HIPEC), concepts like high pressure,  use of vasoconstrictors or hypo-osmolarity, semi-open techniques, use of a heating cable instead of an external circuit, etc, have all been improved by this group in the last 15 years.
  2. Isolated organ perfusion of chemotherapy (liver or lung). Since 6 years we are dealing with liver or lung unresectable metastases using this approach. Feasibility studies have been performed in a swine model (both for liver and lung perfusion). There is an ongoing phase 1 clinical trial for patients with unresectable liver metastases from colorectal origin.
  3. Intratumoral injection of chemotherapy. This approach is used in experimental models to asses its usefulness in the context of surgical resection in order to avoid an organ sacrifice or as a palliative treatment.
  • Institut National de la Santé Et de la Recherche Médicale
  • Tirets de séparation
  • L'Inserm en région Grand-Est
Support :

Agence Nationale de la Recherche Agrosup Dijon Fondation ARC pour la recherche sur le cancer Cent Pour Sang La Vie CHU Dijon Centre Georges François LECLERC
Conseil Régional de Bourgogne Délégation régionale à la recherche et à la technologie Institut National du Cancer ELA Association Européenne contre les leucodystrophies EPHE : Dijon - Université de Bourgogne Faculté de Médecine de Dijon
UFR Pharmacie - uB, Dijon Fondation de France Fondation pour la Recherche Médicale en France Laboratoire d’excellence - LipSTIC Dijon La Ligue Contre le Cancer Société française d'hématologie