Radiotherapy (RT) is known to induce a local inflammatory response, that triggers multiple parts of the immune system. Stimulator of Interferon Genes (STING) is an endogenously expressed protein involved in innate immune activation through sensing cytosolic DNA by the cGAS-STING pathway. It is well-established that RT of tumor tissue can result in accumulated cytosolic DNA in cancer cells due to a dysfunctional DNA damage repair system. How and to what extent the cGAS-STING pathway and subsequent immune activation is essential for a proper anti-tumoral response has not been fully elucidated.

We specifically study the effects of proton and photon radiation in various syngenic mouse tumor models with the focus on expanding our mechanistic understanding how DNA damage responses, STING-activation and immune modulation interplay.

Plasmacytoid dendritic cells (pDCs) are rare, unique immune cells that only make up 0.1% of human peripheral blood mononuclear cells (PBMCs). They rise from a lymphoid progenitor cell and falls within the group of innate lymphocytes due to their broad immunological functions in modulating both the innate and adaptive immune system. In contrast to their well-described role in antiviral defense, little is known about pDC function and biology in cancer. Some reports indicate that pDCs are present in tumor tissue and can be correlated with both a positive and a negative outcome for cancer patients. Some speculate that this can be linked to whether activated pDCs has the ability to directly kill cancer cells or not – which is a known feature against virus infected cells.

Within our group we have multiple ongoing projects aiming to expand our understanding of pDCs in relation to tumor regression and more importantly pDCs function in direct killing of cancer cells. We use in particularly a human stem-cell derived CD34+ to pDC model, where genetic modifications can be introduced to specifically address different genes effect on the pDC functions. We furthermore use murine stem-cells and in vivo models to ask more complexed questions for how pDC control infections and cancer.

For cancer patients who are selected for Immune Checkpoint Blockers (ICBs), we hypothesize that low immune functionality can be unfavorable for therapy response rates. Importantly, the patient immune competency is not static and depends on physical well-being, obesity/metabolic dysfunctions, and the age/sex factors. We envisage that a holistic assessment of a patient immune competency is critical to accurately determine treatment efficacy.

We participate in different clinical projects where liquid biospies (e.g. blood samples) are collected continuously after treatment initiation. From these liquid biopsies we cryopreserve PBMCs as well as plasma samples. These samples are subsequently used in different bioanalytic assays to assess immunological functionality and capacity, thereby generating a landscape of the individual patient immune competence and fitness. 

The ultimate goal of our research is to improve our clinical models used to determine how, and select when, treatment regimens are planned by incorporating host status factors and the immune fitness profile.

Despite recent great advantages in lung cancer treatment commenced by the usage of check-point immunotherapies, 60 % of patients treated with PD-L1/PD-1 inhibitors remain unresponsive. We believe this is partly due to lack of successful immune activation in the tumor tissue. Therefore, discovery of strategies to trigger the tumor into alerting the immune system is a major research goal and one possible strategy for improving current immunotherapy procedures.

We have various projects ongoing to increase our understanding the complexity of the tumor microenvironment in lung cancer and use this knowledge to develop novel therapeutic strategies that may eventually prone lung cancer to be more reactive to immunotherapy.

The tumor microenvironment often presents itself with a dysfunctional local immune response, preceding tumor evasion and tumor survival. This evasion strategy can be linked to a selective epigenetic regulation of genes, beneficial to tumor survival or detrimental to tumor clearance. We and others have reported that the Stimulator of Interferon Genes (STING) protein is often found downregulated in cancer cells specifically.

The STING pathway is an evolutionary conserved innate immune pathway which main purpose is to senses cytosolic accumulating viral DNA. However, it also becomes activated upon DNA release from Micronuclei and chromosomal instability – two mechanisms often seen in tumor cells. Thus, repression of this factor in cancer cells elicit a novel immunological escape mechanism for the tumor itself.

We have various ongoing projects in the lab trying to understand better how to regulate the STING pathway either through small molecules, indirect activation or even epigenetic mechanisms.