Unravelling the rules for T cell recognition of cancer epitopes

T cells play a crucial role in cancer immunotherapy by targeting and attacking cancer cells. They do so by recognizing specific molecules, called epitopes, displayed on cancer cells but not on normal cells. To maximize the chances of detecting the wide variety of epitopes found across cancer patients, different T cells are endowed with different receptors. T cell receptors recognizing cancer epitopes are promising for therapeutic applications, since T cells can be engineered to express these receptors and infused into patients.

Today, it is increasingly possible to identify the various T cell receptors and the epitopes present in a tumor. However, figuring out which T cell recognizes which epitope is still very challenging. 

In our project, we will combine experimental and computational methods to characterize the recognition of cancer epitopes by T cell receptors. We then aim to develop AI models that can analyze large collections of T cell receptors from patients, in order to identify the most promising ones for clinical use. These results will complement ongoing research at the Department of Oncology and elsewhere, and help accelerate and streamline current pipelines to prioritize T cell receptor selection for T cell-based therapy.

Multisystem cancer biology: targeting the interplay between intra- and extracellular proteostasis

All human cells must assemble – and later break down – the right proteins at the right time and in the right quantities. To do this, they need to use and recycle building blocks such as amino acids, and provide energy for the molecular machines that make and break down proteins. The fine-tuned orchestration of these processes represents a considerable challenge that cells must continually master, as a correct cellular “proteome” (the entire set of proteins) is essential for the proper functioning of cells and for the health of the tissues and organs in which they reside.  As a result, a myriad of diseases often linked to age are linked to the inability of cells to keep the proteome in order.

Cancer cells usually grow and multiply faster than normal cells. They are therefore thought to be particularly dependent on the processes that regulate the proteome in order to keep up with high protein turnover. Disrupting these mechanisms is a promising therapeutic approach and has already led to new treatments for some cancers, such as multiple myeloma, a malignant disease of the bone marrow. Our team is working to better understand how different cancers try to keep their proteome in order, and to find ways to target these mechanisms with new drugs. One of the molecules we are interested in is called GCN2. It regulates how cells respond when their amino acid stores run low. We want to understand how to safely turn off GCN2 in cancer cells so that their proteome fails, killing them, while healthy tissue is largely spared. We know that this approach works well experimentally in some cancer cells, but not in others. One goal of our research is to identify the features that make cancer cells dependent on GCN2, which would help identify cancer patients (prior to therapy) that are likely to respond to treatments with drugs that target GCN2. To do this, we use a so-called systems biology or multi-omics approach, in which different technologies are used to study several cellular processes in parallel (e.g., to understand how cellular metabolism changes when certain genes are actively transcribed and translated into proteins). We and many others believe that such a holistic approach to molecular cancer research has great potential to identify previously unknown cancer cell vulnerabilities. To find and target these Achilles’ heels, we collaborate with academic colleagues and research partners from the biotechnology and pharmaceutical industry.

Mirror Therapy for Phantom Breast Syndrome

Breast cancer is the most frequently diagnosed cancer in women, with more than 6000 new cases diagnosed yearly in Switzerland; an incidence which is still increasing. Although still a leading cause of cancer-related death^1,2, mortality due to breast cancer has decreased considerably over the last decades^1,2, thanks to the implementation of mammography screening programs, surgery improvements, and more efficient medical treatments.

Approximately 40% of breast cancer patients must undergo a mastectomy to treat their disease³. Therefore, the management of long-term consequences of this surgical procedure is advocated, in order to limit the economic and societal impacts of its related morbidity and to improve the quality of life of cancer survivors.

Phantom breast syndrome (PBS), occurring after a mastectomy, is a condition characterized by a residual sensation associated with the removed breast tissue, accompanied by neuropathic pain (similar to phantom limb syndrome after amputation). Although of varying estimated incidence in the literature, its prevalence reaches up to 30% in patients having undergone this procedure³. Accordingly, 760 women are diagnosed with PBS in Switzerland every year. In addition to painful sensations described as shooting and burning, patients may also experience other discomforts, such as pins and needles, itching, tingling, pressure, and throbbing³. PBS severely affects the quality of life as a consequence of the physical disability and emotional distress it generates. Some studies demonstrated that depression, psychiatric morbidity, and fear of cancer recurrence are more important in women suffering from PBS³.

Parallels have been drawn between PBS and phantom limb syndrome, such as the timing of their installment after surgery. There are also clues that their development occurs on the same neurological basis. Research on PBS is still sparse and often inconclusive. However, it is increasingly clear that this condition has its own specificities. Therapeutic interventions for this type of pain include oral medications, such as opiates and antidepressants, in addition to topical agents. However, such medical treatments have limited efficacy once this type of chronic pain is installed. Similarly, preventive treatments aiming at reducing PBS incidence are currently not available. Patients are often isolated with their syndrome, as the awareness of the existence of PBS is limited outside of the specialized medical community, making the management of this syndrome a major unmet clinical need.

In this study, we aim to adapt “mirror therapy”, a common non-invasive treatment for phantom limb syndrome, for the care of PBS patients. This method, effective since the mid-1900s^4,5, relies on the usage of a mirror to hide the amputated limb and to replace its image with the reflection of the intact contralateral limb. By doing so, the patient’s brain is tricked by the visual perception of two functional limbs, which elicits cortical remodeling and subsequent neuropathic pain relief. After decades of research, the therapy has been improved and adapted using different combinations of physical mirrors and virtual reality.

This project aims at improving the quality of life and the performance status of women suffering from PBS thanks to non-invasive devices and accompanying physiotherapy sessions. The objective is to improve pain control and potentially reduce PBS-related disabilities and their economic and societal impacts. This project started a year ago, but requires substantial funding to achieve further improvements.

Chimeric antigen receptor T Cell therapy for children and adults with relapsed acute myeloid leukemia

Press release

Targeting novel molecular networks underlying bladder cancer recurrence and progression

Bladder cancer (BC) is a very significant world public health problem, in terms of prevalence, mortality, clinical management and cost. For most patients (around 70%), the disease is detected as a non-muscle invasive BC (NMIBC) at the surface of the bladder. For many years, it has been treated with BCG instillation and tumor resection within the bladder. This treatment is efficient, but most patients will undergo tumor recurrence and will necessitate several rounds of treatment over the years. The disease can also evolve into muscle invasive bladder cancer (MIBC, 30%). In these cases, the treatment consists in chemotherapy and bladder removal (cystectomy). Despite this radical treatment, the overall survival is low, with half of the patients not surviving beyond five years. Survival does not exceed 15 months when the disease is metastatic. In the last years, the tremendous success of immunotherapy has also led to some success in the treatment of MIBC. Immunotherapy, in this case, will restore the capacity of the immune system to fight the disease. 20 to 30% of the patients treated with antibodies blocking the PD-1/PD-L1 pathway showed a response to the treatment. But this rate of response is lower than in other cancer types and there is a clear need to understand why the patients do not respond to the treatment in order to improve and find new immunotherapeutic treatments.

In this optic, we plan to combine the expertise of our two research teams to decipher the molecular mechanisms driving BC recurrence/progression. We will carry out studies directly in patient samples and in a genetically engineered mouse model (GEMM) of BC that recapitulates the human BC tumor progression stages. Furthermore, we will dissect and validate novel therapeutic axes and biomarkers in this GEMM, in view of phase I/II clinical trials in BC patients to improve patient survival.

Preliminary genetic studies on primary and recurrent tumor tissues of a cohort of 12 BC patients led to the discovery of a gene signature associated with BC progression/recurrence. In our study, we will focus on two pathways found in this signature that can be targeted to improve tumor control/elimination. We validated that these two pathways were higher in recurrent versus non-recurrent tumors in a larger cohort of 36 patients. This same gene signature was also detected in the progressive stage of our BC GEMM, confirming the known clinical relevance of this model. Based on these findings, we hypothesize the existence of a therapeutically targetable crosstalk between immune and BC cells that involves the studied genes and their regulation.

Understanding how clonal hematopoiesis feeds lymphoma

Patients with lymphoma who do not respond to treatment have a bleak outcome. Annually, over 1100 patients die with leukemia and lymphoma in Switzerland. Lymphoma can arise when the DNA inside a lymphocyte changes in a way that prevents the lymphocyte from responding to signals that usually keep it under control. To outgrow and disseminate, lymphoma hijacks normal inflammatory cells to acquire protection and nurturing, while at the same time deceiving them by hiding from their attack. Inflammation may be age-related and can foster manifestations such as clonal hematopoiesis or can be sustained by chronic infections of the lymphoma cell itself.

The new avenues of lymphoma therapy rely on a combination of approaches that target both tumor cells and the supporting host environment, including: i) repairing the operative system inside lymphoma cells, which can be achieved by using small molecules that precisely identify and attack the factors that led to its failure; ii) reverting the stunned inflammatory cells from lymphoma feeders to lymphoma predators. The experiments will also allow us to understand how aging-related inflammation facilitates lymphoma development. We aim to understand how aging of the normal immune functions (designed to cause inflammation) modulate the tumor and the surrounding immune system. Single cell resolution now puts us in the unique position to track the aging of cells of the immune system (locally and globally) and to connect them to the behavior of cancer cells. We will use this knowledge to develop strategies to engage the healthy immune compartment in the fight against the tumor. This is of particular interest as the advent of multiple immunotherapy approaches puts increasing emphasis on the efficacy of drugs on immune responses or the fitness (exhaustion) of the anti-tumor response.

Exploring the role of neutrophils in brain metastasis

The development of metastases unfortunately remains the leading cause of death in cancer patients. Of all metastatic cancers, those invading the brain represent a particularly difficult challenge to treat. Brain metastases (BrM) frequently arise from melanoma, lung and breast cancers. Although considerable advances have been made in treating these cancers at the primary site, a steep increase in mortality is observed in patients who develop BrM. This is partly due to our limited knowledge about the BrM tumour microenvironment (TME), which directly translates into a lack of clinical treatment options.

While the importance of immune and stromal cells in the TME in shaping a favourable environment for tumour growth is well-established, much less is known about the complexity of these interactions during metastasis. This is particularly true for BrMs, where the unique properties of the brain create an environment that is very different to other organs. By comprehensively analysing the TME in diverse brain tumour patient samples, we recently identified neutrophils, the most numerous circulating white blood cell population in humans, as among the most abundant immune cells infiltrating BrM specifically.

The aim of this project led by Prof. Johanna Joyce (Department of oncology, UNIL,
Ludwig Institute for Cancer Research Lausanne), is to unravel how neutrophils may functionally contribute to the colonisation and metastatic outgrowth of cancer cells in the brain. It represents the first in-depth study of neutrophil phenotypes and functions in BrM patients and preclinical models.

The rigorous and integrated experimental strategy devised by the Joyce lab, including both mouse models and human tissue analyses, will provide the first comprehensive view of how neutrophils may regulate metastatic progression to the brain. Neutrophils have generally been associated with poor prognosis in cancer patients, but have also been found to serve opposing functions in other metastatic settings, specifically breast-to-lung metastasis, in a context-dependent manner. By contrast, the role of neutrophils in the context of BrM remains virtually unexplored. Thus, a rigorous analysis of their functions in BrM is urgently needed. The combination of functionally analysing neutrophils in human BrMs and utilising state-of-the-art murine BrM models represents a comprehensive strategy to explore neutrophil education by brain-colonising cancer cells. Critically, these data will reveal how neutrophils in the periphery and the brain TME evolve with, and contribute to, the progression of metastatic cancers. Regardless of whether we discover neutrophils to be tumour-supporting or tumour-suppressing in BrM, this is an essential question to answer, which we are uniquely capable to address.

This project will significantly enhance our understanding of neutrophil functions in metastasis and may have important implications for devising therapeutics to target the BrM TME in the future. The cancer immune-microenvironmental perspective of this project additionally addresses a topic of intense focus at present, as different immunotherapies are rapidly advancing to first-line treatments for many cancer types. However, patients presenting BrMs have been largely excluded from clinical trials, resulting in a critical lack of knowledge for how novel treatment modalities might specifically affect or benefit intracranial metastases. Thus, the advance in knowledge that we expect to achieve through this ISREC-funded project will provide the necessary bridge linking fundamental research on BrM tumour immunity to answering essential clinical questions.

Transcriptomic and phenotypic profiling of the white blood cells in breast cancer

Despite considerable improvements in breast cancer management, approximately one in four patients still die due to metastases. In order to decrease this mortality, the disease needs to be diagnosed as early as possible, and metastases must be prevented or treated effectively. Studies we have conducted show that the presence of breast cancer alters quantifiable phenotypic and transcriptomic characteristics of white blood cells (leucocytes) circulating in the blood. These results suggest that it may be possible to exploit these changes in the leucocytes circulating in the blood to reveal the presence of primary breast cancer (screening) or a relapse (monitoring).

The aim of our project is to generate additional data supporting these observations. To this end, we will use novel approaches and technologies (single cell RNA sequencing and multi-parameter analysis of the cell surface). We plan to compare first-diagnosis female patients with healthy women, and patients at the time of the first relapse after therapy with patients not having suffered a relapse. We will investigate the three biological subtypes of breast cancer (ER⁺, HER2⁺, triple negative). This multicentric study, conducted in the Lake of Geneva area, will be coordinated at the CHUV in Lausanne.

A 20 ml blood sample will be taken for the following lab tests: i) leucocyte phenotyping by flow cytometry; ii) transcriptomic analysis and phenotyping by single cell RNA sequencing, followed by bioinformatic analyses. The lab tests will be conducted at the University of Fribourg, the sequencing at the Genomic Technologies Facility of the University of Lausanne (LGTF) and the bioinformatic analyses at the Swiss Institute of Bioinformatics (SIB).

We hope that these analyses will help us validate our preliminary observations more precisely and that we will be able to identify candidate biomarkers (cells, phenotypes, gene expression) and combinations associated with primary breast cancer or the first relapse.

This study is part of a long-term goal to develop a cancer screening blood test and a monitoring blood test for early detection of relapses. The practical implications of these tests are potentially significant: the tests could contribute to changing the way women are screened and patients monitored, thereby greatly improving the quality of life of women in general (screening) and of breast cancer patients (monitoring). From a clinical point of view, the monitoring test would be a valuable new tool that could help support therapeutic choices in the treatment of breast cancer.

Development of a novel B cell-based vaccine for metastatic solid cancers

It is now well established that the immune system plays a very important role in controlling tumor growth; in fact, the remarkable results achieved in the past few years with the arrival of cancer immunotherapies and checkpoint inhibitors have clearly revolutionized the field of oncology and have dramatically changed the therapeutic scenario in many tumor types. Among the different cancer immunotherapies now available, cancer vaccines focus on the therapeutic use of a special type of immune cells called antigen-presenting cells (APCs). The main physiological role of these cells is to intercept and recognize pathogen-associated and foreign material (called antigens), and to subsequently initiate an immune response aimed at clearing the original antigen-containing threat from the host. Given the pivotal role played by APCs in orchestrating an immune response, it comes as no surprise that this type of cells has been employed since the infancy of modern cancer immunotherapy in the fight against cancer.

Canonical approaches have so far relied on the use of a special type of APCs called dendritic cells (DCs), which have long been considered the most potent type of APCs in the human body. However, despite proving generally safe and being associated with very mild collateral effects, DC-based therapeutic vaccines have so far demonstrated limited therapeutic efficacy. Mounting evidence now suggests that a second type of APCs called B cells present a valid alternative with several advantages. First of all, B cells can be obtained and expanded in large quantities from the human body, while cell availability often constitutes a limiting factor with DC-based vaccines. Contrary to DCs, B cells are also resistant to functional inhibition induced by tumor-produced factors, another aspect often limiting DC therapeutic efficacy. Several previous studies have also shown that B cells are indeed able to induce a potent and cancer-specific immune response.

Based on this collective evidence, our project focuses on developing a novel therapeutic vaccine against cancer, based on B cells. One of the first project goals is to manipulate and engineer B cells to express special receptors that increase their accumulation at the tumor site after infusion into the patient. This aspect is obviously crucial in improving their efficacy against their tumor targets and in limiting off-side and systemic effects. In a second phase, we will test our B cell vaccine formulation in combination with checkpoint blockade inhibitors, another promising immunotherapy with a different and complementary mode of action. Checkpoint blockade refers to specific pathways normally developed by tumors that inhibit T cell activities, exerting a sort of “break” on the function of the immune system and anti-cancer properties. Thus, combining these two therapies constitutes an interesting potential therapeutic option, in which B cells would activate the immune system (more specifically T cells) against tumor targets, whilst checkpoint blockade inhibition would remove inhibitory “breaks” on T cell function and unleash these cells’ true anti-cancer potential.

In the last part of this project and thanks to the infrastructure for translational studies available at the University Hospital of Lausanne and at the Ludwig Institute (Lausanne Branch), we will also develop protocols and tests for an efficient production of our B cell final formulation in a good manufacturing practices (GMP) context, so as to enable its future application in clinical studies and patient tests. The requirements for testing cellular therapies in patients (usually referred to as GMP conditions) are obviously very different and stricter than laboratory bench and animal research settings, and a great deal of work is usually needed to adapt therapy production in order to meet such requirements. Thus, the validation of the findings of this project in a GMP context will pave the way for future translational studies in cancer patients, and will potentially help advance both the therapeutic scenario and clinical outcomes.