CD Laboratory for Activation of Immunogenic Cell Death in Lung Cancer

Cancer cells can be eliminated by the body‘s own immune system, supported by so-called immunotherapies or chemo-immunotherapies, and in many patients, tumours can be controlled in the long term. However, non-small cell lung cancer (NSCLC) remains extremely difficult to treat because it is highly effective at evading this immune defence. This often leads to relapses within months or a few years.

The CD Laboratory for “Activation of Immunogenic Cell Death in Lung cancer” (or ARNICA = Activating Regulated Necrosis In CAncer) investigates therapeutic strategies aimed at making the cancer cells more visible for the immune system, and seeks to identify biomarkers as well as treatment strategies that support this process.

Genomic medicine investigates how healthy tissue undergoes genetic changes that allow cancer to develop. The underlying genetic alterations in NSCLC have already been characterised in great detail. Yet, this leap in molecular understanding of NSCLC has so far not delivered on its promise to markedly improve clinical outcomes for the majority of patients, as NSCLC remains the deadliest cancer worldwide.

In some forms of lung cancer, the mutations that drive tumour growth are known. There are targeted therapies that are very effective against these so-called oncogenic driver mutations or genetic fusions, such as in EGFR, ALK, RET, ROS or KRAS. While controlling lung cancers harbouring mutations in ALK, RET or ROS is feasible for many years, these genetic subgroups are exceedingly rare. The large number of patients with mutations in e.g. EGFR or KRAS relapse after approximately two years. Even more dismal is the outcome of patients without detectable oncogenic driver mutations.

Immunotherapies have improved the outcome of these patients considerably but still fail to provide long term tumour control. Biomarkers robustly predicting response to immunotherapy remain elusive, however, the expression of the PD-L1 protein on the surface of tumor cells helps to identify patients for whom immunotherapy is promising. Lung cancer cells with high PD-L1 expression can evade cellular attach by T lymphocytes. Immunotherapies, such as PD-L1 or PD-1 inhibiting antibodies, can make these tumour cells visible to the immune system again. An improvement of progression-free survival times of lung cancer patients of up to 12 months is the result depending on expression level and patient characteristics. Since patients with low PD-L1 expression require additional toxic chemotherapy to improve outcomes over the level of immunotherapy alone, the research in this CD-Lab aims at identifying new treatments and biomarkers that can predict which NSCLC patients will respond to immunotherapy particularly well and how to improve treatments.

Recurrences – the main obstacle to long-term survival in NSCLC patients – are largely driven by immune evasion of the rapidly changing tumor cells that prevent sustained immune recognition. This is curious, as NSCLC has many characteristics that can be recognised by the immune system, i.e. it has a high number of potentially immunogenic mutations. Nevertheless, unlike melanoma, NSCLC cannot typically be controlled in the long term by immunotherapy because the cancer finds ways to bypass destruction by immune cells.

Immunogenic cell death (ICD) is a specific form of programmed cell death where a cell dies in a manner that alerts the immune system. This mechanism is often suppressed in cancer cells, contributing to immune evasion. Targeted activation of ICD could therefore enhance immune recognition of NSCLC. By intervening in ICD-regulating signalling pathways, tumour detection and destruction by the immune system could potentially be improved. However, achieving this requires a deeper understanding of the molecular mechanisms of ICD in NSCLC, which represents the goal of this CD Laboratory.

Using data from clinical cohorts and state-of-the-art cancer models and technologies, this research project will provide important insights into the molecular processes of ICD and develop strategies for its targeted activation in lung cancer. The focus lies on the two major ICD signaling pathways of necroptosis and pyroptosis.

The research objectives lie in the identification and validation of target molecules as well as in biomarker analysis in NSCLC. The CD Laboratory will leverage expertise in basic research, translational science, clinical expertise, bioinformatics, and pharmaceutical know-how to identify novel drug targets and biomarkers in lung cancer.

A wide range of technologies and model systems will be used, ranging from primary human NSCLC patient samples and advanced mouse model systems to CRISPR-Cas9-based in vitro and in vivo screenings (including CRISPR activation) as well as NSCLC organoids and tumour fragments.