Treating cancer remains a long, difficult and not always successful process. Improving diagnosis is curcial both to early detect cancer when it is more easily treated and to better characterize detected tumors to identify the most appropriate therapeutic strategy. At the Institut Pasteur we are developing new tools to improve diagnosis using cutting edge computational biology, combined with the identification of new prognosis markers. Recent data show that the intestinal flora influence treatment efficacy. Pasteur research teams aims at identifying bacterial components which could be used to improve existing treatments.
Department of Cell Biology & Infection
Recent work of the unit has uncovered a key role for the post-translational modification of proteins by the smal protein SUMO in the control of innate immunity. Inhibition of sumoylation notably triggers a massive type I interferon (IFN-I- response) that acts in synergy with anti-PD1 immunotherapy to improve antitumor response. These results open new perspectives for therapeutic targeting of the SUMO pathway in human cancers.
Department of Genomes and Genetics
This group has developed powerful microfluidic tools to produce, manipulate, and observe three-dimensional cell cultures, such as spheroids or organoids. These culture formats lend recapitulate in vivo cellular functions far better than traditional 2D cell culture, by recapitulating the physical and chemical 3D micro-environment. They are currently exploring how these tools can lead to new insights on cancer treatments in different situations, in collaboration with groups at the Institut Pasteur and elsewhere. For example, they are studying the response of model tumors to combinations of drugs, in order to discover potential drug synergies. They are also studying the interactions of tumor spheroids with T-lymphocytes at the single-cell level, in order to evaluate the effect of the 3D structure of solid tumors on the ability of T-cells to kill them.
Department of Immunology
Tumor immune surveillance and immunotherapies
This unit is using functional in vivo imaging to dissect mechanisms of tumor immune surveillance at the single cell level and identify the mode of action of tumor immunotherapies (such as tumor targeting Ab, CAR T cells and checkpoint inhibitors). This team is also investigating how spontaneous or induced anti-tumor immune responses shape intratumoral genetic heterogeneity.
Key words: cancer immunotherapy, CAR T cells, therapeutic antibodies, immune checkpoint blockers, intraclonal tumor heterogeneity, imaging
Inhibitors of protein translocation to treat cancer
This team has recently demonstrated that mycolactone, a bacterial lipid toxin, operates by targeting the mammalian translocon (Sec61). Using this tool, the scientists are testing the hypothesis that by triggering proteotoxic stress and altering tumor cell communication with the environment, mycolactone-mediated Sec61 blockade may potentiate the therapeutic activity of proteasome inhibitors in the treatment of Multiple Myeloma.
Key words: sec61 translocon, therapeutic target, proteotoxic stress, multiple myeloma, combination therapy
Notch, a promising treatment for hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the main liver cancer, and the 3rd leading cause of cancer death worldwide. Transplantation is the best treatment, but it is not available for numerous cases of patients. Even while waiting for a transplant, it is essential to slowdown the progression of the cancer and then to support the immune system to fight tumors.
Notch is one of the pathways in consideration for anti-cancer therapies. A phase I clinical trial targeting Notch is under investigation for the treatment of HCC. In addition to its role in limiting hepatocyte proliferation, this pathway may act on the intratumoral immune compartment functions as it conditions the differentiation and maturation of lymphocytes in the normal state. No studies have yet evaluated the effect of anti-Notch therapy on hepatic immune populations in HCC.
Patients with HCC have an unexplained suppression of lymphocyte antitumoral functions. NK lymphocytes (Natural Killer) and ILC1 (Innate Lymphoid Cell 1) are known to promptly fight tumors and their functions are disrupted during HCC. We are evaluating the modulation of the antitumoral lymphocyte functions generated by the Notch pathway, in particular for their cytotoxic and inflammatory functions. By using a combination of molecular and cellular technologies, we propose to decipher the interactions connecting the Notch pathway to the modulation of lymphocyte anti-tumoral functions.
Our long term goal will be to propose new effective immunotherapeutic strategies that could act on key molecules along the antitumor signaling axis related to the Notch signaling pathway. The development of immunotherapeutics targeting the Notch pathway axis will allow new options. Current "immune checkpoints" treatments have modest results in case of HCC and new combinatorial alternatives are needed to efficiently re-boost cells of the immune system. It is crucial to increase the richness of the therapeutic arsenal while this cancer is constantly increasing across the world, due to new eating habits and the increased numbers of cirrhosis.
Key words: hepatocellular carcinoma, ILC response to cancer, notch signaling in liver cancer, regulation of antitumoral response
Milena Hasan (CB UTechS)
The Cytometry and Biomarkers Unit for Technology and Service (CB UTechS) and Cancer Research
The Cytometry and Biomarkers Unit for Technology and Service (CB UTechS) is a core facility at the Institut Pasteur with the mission of supporting scientific projects through innovative technologies for cellular phenotyping and sorting, molecular profiling and experimentation at single cell level. The technologies are installed within Bsl2/3 laboratories to allow manipulation of human and /or infected material. This unique configuration enables full response to a scientific question, from sample processing to data analysis. The CB UTechS is an open-access platform, that hosts projects from academia and industry and provides support through training, service, development and an interaction with clinical project managers for clinical research studies. The quality of services is ensured by iso9001 certification. The CB UTechS supports numerous tumor-research-related projects. These include both clinical and translational studies focused on innovative cancer therapies and on cancer and microbes, as well as fundamental studies of cancer biology. These projects benefit from the integrate support established at the CB UTechS to ensure all necessary tools for addressing different topics in the context of cancer research.
James di Santo / Christian Vosshenrich
NK / Innate Lymphoid Cell (ILC) responses to cancer
We aim at identifying novel genes involved in ILC/NK cell-mediated regulation of tumor immunity. To achieve this, we use the Collaborative Cross(CC) mouse resource, which represents a large collection of recombinant inbred mouse lines combining high genetic diversity with the advantages of inbred lines making it an ideal tool for functional genetic mapping studies. We performed a comprehensive analysis of NK cells in CC mice revealing large phenotypic and functional variation for key NK cell traits and discovered several QTLs driving this (Dupont et al., 2021). These results are the foundation for our search for novel mechanisms regulating the anti-tumor response of NK cells. The novel genetic mechanisms of NK cell immunity, if actionable, will be used to develop novel anti-cancer therapies.
Key words: innate Immunity, NK cells, ILC, quantitative trait locus mapping, mouse model
Stromal microenvironment and cancer
This lab is interested in the role of the stromal microenvironment in tumor progression/immunity and resistance to therapy, with a focus on melanoma, pancreatic cancer and breast cancer. Using different experimental approaches, we are investigating at the single cells level the crosstalk of tumor stromal cells - such as CAFs, fibroblasts and pericytes- with infiltrating immune cells and cancer cells. Our research aims at better understanding the cellular and molecular mechanisms underlying tumor development and immunity, as well as identifying novel (co)-therapeutic approaches in cancer.
Key words: tumor stromal microenvironment, CAFs, immunotherapies, cancer biology
Immunotherapy for bladder cancer.
Bacillus Calmette-Guérin (BCG) instillation has been the standard-of-care for nonmuscle invasive bladder cancer, the fifth most common malignancy in Europe and the U.S for 40 years and is one of the most successful immunotherapies in use today. Nonetheless, 30-50% of patients fail to respond to BCG immunotherapy and models to understand this are lacking. This team is developing novel bladder cancer models in which mechanisms of action of known and novel mono and combination immunotherapy can be dissected, and T cell priming and effector function be followed directly. Its goal is to improve cytotoxic T cell function to improve tumor immunity. With this knowledge, the scientists can rationally design combination immunotherapeutic approaches to reduce the incidence of BCG unresponsiveness or tumor recurrence, potentially establishing alternatives to surgical resection and chemotherapy, leading to improved patient outcomes.
Key words: bladder cancer, immunotherapy, immune memory, BCG
Department of Microbiology
Ivo Gomperts Boneca
Adjuvant effects of the commensal flora on chemotherapy and immune checkpoint inhibitors therapy during cancer treatment
The efficacy of chemotherapy and novel immune checkpoint inhibitors is dependent on the commensal flora. However, this efficacy is variable from patient to patient and dependent on the presence of certain members of the commensal flora while others might have deleterious effects. They have been dissecting the beneficial role of Enterococcus hirae on chemotherapy by cyclophosphamide, the innate immune receptors involved in the mode of action as well as the cell types involved using state-of-art imaging techniques to track live bacteria as well as individual components of the bacterial cell wall combined to transgenic mice.
Key words: microbiota, chemotherapy, Enterococcus hirae, oncobiotics, innate immunity
Department of Neurosciences
Role of human polymorphisms in nicotinic receptor genes in the predisposition to COPD and lung cancer
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality, with exacerbated inflammation leading to progressive airway obstruction and emphysema, typically linked to smoking. Genome-wide Association Studies (GWAS) identified a human haplotype including a single nucleotide polymorphism (SNP) in the CHRNA5 gene (α5SNP) encoding nicotinic acetylcholine receptor (nAChR) subunit α5, linked to both smoking and COPD. α5SNP directly contributes to COPD pathology and carcinoma, sensitizing the lung to the action of oxidative stress, and represents a novel target for therapeutic strategies.
Key words: lung cancer, chronic obstructive pulmonary disease, human genetic polymorphisms, nicotinic receptor
Enhanced visualization and immersive control of cancer imaging technologies
The scientists are developing a software platform DIVA that joins human cognition, algorithms and virtual reality to analyze complex 3D images. DIVA is currently used for cancer surgery planning by providing enhanced visualization and immersive control of MRI and CT scan. Their new initiatives are focused on one shot learning in virtual reality to annotate and segment complex MRI data stemming from multifocal cancers. Finally, DIVA is used to analyze microscopy data from lab experiments.
Key words: segmentation free analysis, children medical imaging, breast cancer surgery, surgery planning
Department of Structural Biology and Chemistry
Project #1 - Targeting the NEMO protein: an innovative strategy to develop new anti-cancer drugs
In most cancers, the NF-kB pathway is constitutively active as a cause or a consequence of the tumor process. An important part of the research on inflammation and cancer is based on the development of therapeutic strategies for tumors focus on the selective inhibition of this pathway. This strategy is based both on an approach aimed at targeting the central regulating element of this activation process, the NEMO/IKK complex and the search for new regulators of NF-kB by an innovative strategy.
Project #2 - High content phenotypic screening for cytokinesis by targeting the CEP55 protein and its functionally related ubiquitin ligases and deubiquitinases: an innovative strategy in anti-cancer drug discovery
Research on cell division is important because an improved understanding of its mechanism could lead to improvements in the treatment of diseases such as cancer. Cell division terminates with the separation of the replicated genomes (mitosis) and cytoplasms (abscission), yielding two daughter cells. This laboratory focuses on the development of abscission inhibitors by targeting the CEP55 protein and its functionally linked ubiquitin ligases and deubiquitinases identified by siRNA ubiquitome screen, since any active substance that alters these proteins' functions would allow the development of next-generation anti-cancer drugs.
Aberrant epigenetic patterns are involved in tumor formation, maintenance and resistance. Notably, epigenetic modifications can be modified by chemical agents. In this context, this unit develops an original approach at the interface of chemistry and biology to identify new inhibitors of DNA and histone methylation. These chemical tools constitute an alternative approach to address the biological questions in the understanding of cancer formation and maintenance. For example, an important open question in cancer is what specifically hypermethylates tumor suppressor genes in cancer cells when a global hypomethylation is observed? DNMT inhibitors can be used as chemical probes to address this question. Thus Epigenetic Chemical Biology (EpiChBio) focus on:
1/ the design of chemical molecules targeting DNA and histone methylation,
2/ their use as probes to scan the molecular process that deregulates these modifications in cancer and
3/ their use as potential therapeutic agents to reprogram gene regulation in cancer cells.
A precise elucidation of why the methylation processes is aberrant in cancer is the key to a better understanding of the disease and to fight it. The understanding of these processes will open the way to the discovery of novel anti-cancer targets, eventually also biomarkers, and innovative therapeutic strategies.
Key words: epigenetics, DNA and histone methylation, inhibitors, chemical probes
Non-Homologous End Joining (NHEJ) is one of the main mechanisms in the cell for the repair of double-strand breaks (programmed or not). The scientists are conducting structural studies to characterize at the atomic level the complex of Ku 70/80, DNA polymerase mu and DNA, which is an important part of the macromolecular assembly responsible for NHEJ.
Their aim is to use the structure of the complex to design drugs directed at the interface between the different partners, so as to shut down temporarily the NHEJ response to DNA damage. In particular, such a drug taken in conjunction with radio-therapy would considerably increase the efficiency of radiotherapy during cancer treatment.
The current effectiveness of treatments for cancer varies greatly. However, regardless of cancer type debilitating side effects of treatment are near-ubiquitous. One treatment modality for cancer is photodynamic therapy (PDT) in which a photosensitizer (PS) is administered to the patient and is only cytotoxic upon application of light. However, current PSs suffer from limited target specificity leading to undesired levels of healthy tissue damage. This team addresses this lack of specificity by combining PSs with aptamers, which are short DNA molecules with high binding affinity to given targets. To this effect, a library of oligonucleotides coupled to a Ruthenium-based PS has been prepared using a modified nucleotide. They will use this modified DNA library in both a targeted strategy against the protein SIRT2, a histone deacetylase that has been recently shown to play an important role in c-myc dependent cancers, and in a global approach against colorectal cancer cells. The specificity and cell death activity of the PS-aptamers will be evaluated in vitro in a project novel in both its approach and in generation of tools with high therapeutic potential.
Key words: modified aptamers, therapeutic oligonucleotides, photodynamic therapy, drug delivery systems
Design of fluorescent peptides for the in cellulo and in vivo imaging of tumor-associated receptor guanylyl cyclase C
Guanylyl cyclase C (GC-C) is expressed in intestinal epithelial cells and is a major regulator of fluid and ion secretion in the gut. Undoubtedly, fluorescent probes retaining GC-C binding would prove invaluable in tracing cells expressing GC-C in vivo and provide essential insights on GC-C associated diseases, including cancer. For example, metastases of colorectal cancer result in extra-intestinal tumors that express high levels of GC-C. Such labeled probes derived from natural GC-C peptide ligands are under development. Moreover, they could also serve to develop assays to screen for inhibitors of colonic tumors.
Carbohydrates as tumor markers
Carbohydrates are well-established tumor markers. As such, synthetic oligosaccharides, glycopeptides and conjugates thereof are of high interest for the development of diagnostic tools or therapeutic vaccines (see for example the MAG-Tn3 vaccine candidate in phase I against breast cancer, S. Bay). Ongoing external collaboration on another system.
M. Nilges / O. Sperandio
We aim to identify and prioritize new therapeutics targets against in disease-associated pathways related to cancer by rationalizing the concept of druggability for protein-protein interactions (PPIs) according to the properties of their interfacial binding pockets. Using a combination of chemoinformatics and structural bioinformatics and artificial intelligence technologies, the interfacial binding pockets of all structurally characterized PPIs in the Protein Data Bank (PDB) are mapped. This information is then combined with other data sources: hot spots, phylogeny, nsSNPs, biological networks, and cancer-associated protein mutations. The purpose is to establish a full cartography of the PPI pocketome with predicted and experimental annotations that could provide new options for therapeutics intervention in the field of cancer.
Department of Virology
Upon lentivector based vaccination, peptides derived from the vaccinal antigen are stably presented by MHC molecules at the surface of DC, through the endogenous presentation pathway, hereby allowing intense tumor specific T cell initiation.
The ultimate goal of this team is to initiate human clinical trials of anti-tumoral therapeutic vaccination for several indications. New generations of non- integrative lentivector (LV) are currently being evaluated in the Pasteur-TheraVectys joined unit for the treatment of HPV-associated cancers and Prostate cancer. We have shown that single dose of therapeutic LV based vaccine very efficiently eliminates large size implanted tumors in 100% of animals. Tumor elimination is persistent, and mice are protected > 90 days against tumor cell re-challenge showing that an efficient long-term T cell response is maintained, susceptible to control tumor relapse.
In collaboration with Fudan University (Shanghai, China), they are also currently optimizing neoantigens approaches in hepatocarcinomas mice models. Tumoral neoantigens are created by somatic mutations within the tumors, these antigens are thereby very specific of tumors and are perfect targets to develop personalized, patient-specific, therapeutic vaccines for cancer. Preliminary studies have demonstrated a strong T cell activation in mice after vaccination and anti-tumoral efficiency of these vaccines will be tested soon.
Therapeutic vaccines against other cancer indications are also currently developed through animal proof of concepts, such as Colorectal cancer (CRC) and pancreas cancer, using genetically induced CRC and pancreas transgenic mice models.
The Unit has developed a virus technology to treat multiple types of cancer. This technology is derived from the safe and highly immunogenic measles vaccine virus, which has clinically proven natural oncolytic potential. They have developed MVdeltaC, a genetically modified virus with improved immuno-oncolytic capacity. This innovative technology allows modulating the natural anti-cancer and immunogenic power of a harmless vaccine virus, making it a versatile platform for cancer treatment. MVdeltaC has demonstrated highly efficient in a panel of pre-clinical studies in vitro and in vivo. Not only does the virus specifically target and destroy cancer cells, but it also has the potential to elicit strong and long-lasting anti-tumour immune responses. With this platform, they aim to develop therapies against several cancer indications, such as mesothelioma (asbestos cancer), bladder cancer, platinum-resistant ovarian cancer, multiple myeloma and others. We believe that this therapy based on a natural non-chemical bio-product derived from the most widespread human paediatric vaccine should gain very positive perception from patients and physicians. This technology will be part of the armamentarium of new revolutionary cancer treatments that will provide patients and medical doctors with chemotherapy-free regimens that will not only have a strong impact on survival, but also on quality of life.