WEHI Special ACRF Cancer Biology & Stem Cells Seminar hosted by Professor Kate Sutherland

Thales Papagiannakopoulos
Department of Pathology; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA

Dissecting the crosstalk of nutrient sensing, stress response signalling and immune evasion

Davis Auditorium

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Including Q&A session

A common feature of many cancers is their ability to evade immune recognition, which is the primary reason for failure of many cancer therapies, including immune checkpoint inhibitors. Despite extensive efforts to characterize drivers of immune evasion, the underlying biological mechanisms remain poorly understood. Most cancers are characterized by a complex tumor microenvironment (TME) with restricted nutrient availability. To adapt to the metabolic limitations of the TME, tumor cells hijack multiple stress response pathways that can regulate many hallmarks of tumorigenesis including immune evasion. However, the mechanisms underlying metabolic adaptation, stress response pathway regulation and suppression of anti-tumor immune responses remain largely unknown.

Using genetically engineered mouse models we are systematically dissecting the mechanisms by which stress response pathways promote tumor growth by reshaping the immune microenvironment. We observe that the major stress response transcription factors are required for the growth of tumors in an immunocompetent setting by suppressing T cell anti-cancer immune responses. Using CRISPR/Cas9 libraries focused against stress response signaling, we performed in vivo genetic screens to dissect the mechanisms driving immune evasion. Our results demonstrate that distinct tumor-derived stress response mediators are secreted and promote immune evasion and tumor progression. These data reveal a previously unidentified role of stress response signaling in suppressing anti-tumor immune responses. To target one of these newly identified secreted factors, we have generated novel blocking antibodies that display therapeutic efficacy. Overall, our studies shed light on the crosstalk of nutrient sensing, stress response signalling and immune surveillance.

All Welcome!