Tumor-specific immunity occurs in cancer patients but has insufficient potential to control or eliminate the tumor. Strengthening this response through immunotherapy may lead to a durable, systemic response that may also control (development of) metastases. However, many hurdles preclude the induction of protective anti-tumor immunity, including clonal deletion of high-affinity, self-reactive T cells, insufficient innate immune signals in the context of cancer and the hostility of the tumor-environment towards protective immunity resulting in compromised T cell function.
A considerable proportion of tumor tissue consists of recruited and resident cells – often referred to as tumor microenvironment (TME) or stroma – and in fact, tumor progression and response to standard as well as immune therapies are strongly influenced by the TME. T cells are the best-characterized population in the TME, both CD4+ and CD8+ T cells can prevent tumor outgrowth, and a high density of activated CD8+ T cells in the TME is associated with better prognosis and therapy response. The TME, however, negatively influences the function of T cells by various mechanisms including immune checkpoints (PD-1, CTLA-4, Tim-3, TIGIT and others) and immunosuppressive cell types as well as cytokines.
Immunotherapies that mobilize tumor-specific, adaptive immunity show significant clinical efficacy and are considered a major breakthrough in cancer treatment. For example, treatment with antibodies that interfere with immune checkpoints such as anti-CTLA-4 and anti-PD-1 has shown objective clinical responses in patients with various cancer types and is just one example of how targeting the TME can translate into clinical benefit.
The main goal of our laboratory is to better understand the mutual interaction between the immune system and cancer and how this interaction changes after therapeutic interventions. We think that this knowledge enables a better engagement of the immune system during standard or immune therapies, which will increase the clinical efficacy as well as the durability of such therapies.
1. The impact of radiotherapy on immune activation
Conventional RT is given as multiple fractions of 1.5-2 Gy during several weeks, but technical advances allow application of radiation in few or even single high-dose fractions. Recent data including our own suggest that whereas conventional radiotherapy induces a chronic inflammatory response that is detrimental to protective immunity, the acute inflammation resulting from single high-dose radiotherapy promotes immune activation (Surace L, et al., Immunity 2915; Surace L, et al., Oncotarget 2015). Although around 40% of all cancer patients will receive radiotherapy at some point, our current knowledge about how different, clinically relevant radiotherapy regimens impact on protective immunity and metastasis in the context of cancer is insufficient.
Our first aim is an in-depth comparison of the clinical and immunological response to conventional and single high-dose radiotherapy. Identifying conditions that promote protective immunity presumably will improve the efficacy of radiotherapy as well as the sustainability of the clinical response. Importantly, such optimized conditions will allow a more efficient combination with immune checkpoint inhibitors.
Our second aim will address innate immune activation by radiotherapy with a focus on defective innate DNA-sensing as immune escape mechanism.
Our third aim will elucidate how different radiotherapy regimens influence the composition and function of tumor-derived exosomes (TEXs). TEXs function as means of long-distance intercellular communication between cells/organs and have recently been implicated in metastasis.
2. Tertiary lymphoid structures and immune defense against cancer
Tertiary lymphoid structures (TLS) in the tumor microenvironment have lately gained attention because of their significant correlation with improved survival in several tumor types. TLS were first described in autoimmune and transplant rejection conditions, where they support the infiltration and activation of adaptive immune cells. We recently observed a beneficial effect of high numbers of germinal center positive TLS on the disease-free survival of non-small cell lung cancer (NSCLC) patients and identified a specific niche that promotes development and maturation of tumor-associated TLS. We thus think that the formation of TLS in tumor microenvironment could promote anti-cancer immunity. Our knowledge about the responsible cell types and signals inducing TLS formation in tumor tissues, however, is limited.
The aim of this project is to investigate whether deliberate induction of TLS may represent a novel stand-alone therapeutic approach or as a means to improve the immune checkpoint blockade therapies. We will use a mouse lung cancer model to analyze the impact of TLS induction on survival and tumor-specific immune response.
3. Beta-catenin/Wnt signaling in non-melanoma skin cancer
Squamous and basal cell carcinoma (SCC, BCC) are frequent skin cancers. Wnt signaling is one of the few known molecular pathways regulating SCC initiation and progression. However, Wnt signaling is an also important regulator of normal skin homeostasis. The key downstream molecule of Wnt pathway is β-catenin, which attracts - via its N- and C-terminus - specific transcriptional co-activators to Wnt-responsive elements and thus activates Wnt-mediated transcription. In addition, β-catenin is an important component of adherens junctions. Such a structural role might be important to maintain the integrity of skin epidermis.
Our focus is to determine the contribution of signaling versus structural roles of β-catenin in development and homeostasis of normal skin and skin cancer.
4. The role of immune cells in different steps of the metastatic cascade
Metastasis is the major cause of death associated with solid tumors. It is becoming increasingly clear that metastases may develop very early, i.e. before the primary tumor becomes clinically apparent and that such metastases may remain in a dormant state for a considerable time.
Primary tumors are often curable by surgical resection or controllable by conventional therapies including radio- and chemotherapy. As the latter therapies mainly target dividing cells, dormant metastases presumably are insensitive to such treatments, whereas they can still be targeted by T lymphocytes. The interaction between the adaptive immune system and developing, early metastases is almost impossible to study in humans and most available data from preclinical models were produced using i.v. injected tumor cells as model for metastasis to the lungs. The biological relevance of such an approach, however, is unclear. Furthermore, this experimental set up does not allow a direct comparison of immune events within the primary tumor and the metastatic lesion.
We therefore use different models for spontaneous metastasis to study three aspects of metastasis: (i) dormancy, (ii) the pre-metastastic niche, and (iii) the involvement of NK and NKT cells in protection against liver metastasis.
5. The role of tumor-derived exosomes in metastatic malignancies and the influence of chemo- or radiotherapy thereon
Intercellular communication is important in steady state and disease and can be mediated by either small molecules such as hormones and growth factors or via direct cell-cell interactions. A mechanism, which has been overlooked, is the intercellular communication via extracellular vesicles like exosomes. Exosomes are nano-sized membrane vesicles with a diameter of 50-120 nm that can be released by all cells investigated. Tumor cells release large quantities of TEXs, which are especially enriched in the blood plasma from cancer patients compared to healthy controls. The exosome concentration in the plasma correlates inversely with survival. In addition, it was recently demonstrated that TEXs play an important role in preparing the pre-metastatic niche. However, many open questions remain, such as how TEX contribute to the pre-metastatic niche, how TEX promote metastatic seeding and progression, or which receptors on endothelial and epithelial cells are involved. Finally, whether TEX modulate the clinical response to standard or immune therapies is currently unknown.
In this project we aim to answer following questions: (i) Do TEXs from metastatic and non-metastatic cells differ with respect to homing to (pre-metastatic) organs and attraction of immune cells? (ii) Do standard therapies impact qualitatively or quantitatively on TEXs?
Methods and techniques
- A wealth of pre-clinical tumor models (transplantable, autochthonous, spontaneously metastasizing) and relevant immunological and clinical read outs for tumor progression and therapeutic response.
- High-dimensional flow cytometry (FACSymphony)
- Quantitative pathology for up to 6 parameters (Vectra)
- Isolation and characterization of exosomes
- Samples (FFPE tissue, fresh tissue, blood) including clinical records from large and well-characterized patient cohorts
- Standard techniques for immunology, biochemistry and molecular biology
- Unrestricted access to various core facilities including microscopy, flow cytometry and functional genomics.
Link to a presentation: