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Karl Landsteiner Lecture 2015

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Stressed Out: A Novel Approach to Cancer Immunotherapy
One target – two anti-cancer strategies!

On April 27th Laurie H. Glimcher, Dean of Weill Cornell Medical College delivered this year’s CeMM Landsteiner Lecture with the topic “Stressed Out: A Novel Approach to Cancer Immunotherapy”. In her lively and fascinating talk, Laurie H. Glimcher presented a novel approach to cancer immunotherapy that looks promising to treat solid, very aggressive, and unfortunately often late diagnosed tumors like breast or ovarian cancer. Her talk attracted more than 300 people to the Festive Hall of the Austrian Academy of Sciences, among them institute heads, scientists, students and scientifically interested citizens. The Landsteiner Lecture was framed by music and followed by a cocktail reception. 

This year’s Landsteiner Lecture held by Laurie H. Glimcher, Dean of Weill Cornell Medical College focused on the disease of the 21st century: Cancer and a novel idea to treat it. Aggressive tumors find creative ways to survive under various stress conditions including hypoxia, nutrient deprivation and chemotherapy. In her talk, Laurie H. Glimcher presented new findings on how very nasty tumors which  are often diagnosed only at late stages like ovarian cancer or the very aggressive triple negative breast cancer, can get stressed out and defeated by the immune system. One could think of two strategies to achieve that: either to target the tumour directly or to activate the immune system to recognize tumour cells as foreign and initiate a robust anti-tumour response. Both approaches can be accomplished by directly targeting a transcription factor called X-Box binding protein 1 (XBP1) that tumors use for their benefit.

Glimcher presented stunning results from her lab showing that XBP1 is not only able to activate pro-cancer-genes but is also highly overexpressed in extremely aggressive tumours rendering it an ideal drug target. Glimcher showed that the silencing of XBP1 in patient derived triple negative breast cancer cells that were subsequently transferred into mice, not only prevents tumour progression but also cancer relapse in these animals. Additionally, silencing of XBP1 enhanced the susceptibility of non-responsive triple negative breast cancer cells to chemotherapy opening a new therapeutic angle. 

Another approach to defeat cancer is to activate the immune system. Cancer cells have developed  strategies to circumvent  this by promoting an immunosuppressive microenvironment surrounding solid tumours. Laurie H. Glimcher explained this with the example of ovarian cancer, which constitutes the 5th leading cause of death in women. 50 percent of cells surrounding ovarian cancer are leucocytes, mainly immunosuppressive dendritic cells. Paradoxically, dendritic cells are potent activators of Type 1 T cells which are able to kill tumour cells. But why do they act immunosuppressive in ovarian cancer? Interestingly, Glimcher disclosed that it is the tumour’s microenvironment that triggers XBP1 activation in dendritic cells via the cells so called ER stress response pathway. XBP1 in turn acts in a way that prevents dendritic cells from presenting tumour specific antigens to T cells, in order to activate them, thus acting in an immunosuppressive manner. Scientists in Glimcher’s lab could demonstrate that silencing of XBP1 in these dendritic cells in mice, promotes antigen presentation to T cells, resulting in increased T cell production and enhanced anti-tumour immunity. 

Taken together Laurie H. Glimcher presented XBP1 as a novel very promising target tor cancer immunotherapy which is especially relevant for treating aggressive solid tumours via two anti-cancer mechanisms:  preventing tumour growth and/or activating the immune system to kill tumour cells. We thank Laurie H. Glimcher for her very interesting and inspiring talk.