Tumor cells dying of ferroptosis limit cDC1-mediated anti-cancer immunity — ASN Events
  1. Schedule
  2. Poster Session 2
  3. Tumor cells dying of ferroptosis limit cDC1-mediated anti-cancer immunity

Tumor cells dying of ferroptosis limit cDC1-mediated anti-cancer immunity (#253)

Lukas Ramsauer 1 2 , Anna-Marie Pedde 1 2 , Anna Hirschberger 1 2 , Maria Parra Reyes 3 , Nadine Nuschele 3 , Felix Bayerl 3 , Sainitin Donakonda 3 , Benedikt Spitzlberger 4 , Martina Anton 3 , Christina M. Bebber 5 6 , Toshitaka Nakamura 7 , Percy A. Knolle 3 , Silvia von Karstedt 5 6 8 , Nicolas Snaidero 9 , Julia Esser-von Bieren 4 10 , Marcus Conrad 7 , Jan P. Böttcher 1 2 3
  1. University of Tübingen; Institute of Immunology, Munich, BAVARIA, Germany
  2. M3 Research Center, Tübingen
  3. Technical University of Munich, Institute of Molecular Immunology, Munich
  4. Technical University of Munich, Center of Allergy and Environment, Munich
  5. University of Cologne, Department of Translational Genomics, Cologne
  6. University of Cologne, CECAD Cluster of Excellence, Cologne
  7. Helmholtz Munich, Institute of Metabolism and Cell Death, Munich
  8. University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne
  9. Hertie Institute for Clinical Brain Research, Tübingen
  10. Department of Immunobiology, University of Lausanne, Lausanne

Type 1 conventional dendritic cells (cDC1s) play a critical role for anti-cancer immunity by priming of anti-cancer CD8+ T cells in lymph nodes and by orchestrating anti-cancer CD8+ T cell responses locally within tumor tissue. Molecular cues sensed by cDC1s upon their interaction with dying tumor cells govern cDC1 activation and determine their ability to instruct anti-cancer CD8+ T cell responses. Induction of ferroptosis, a regulated form of lipid peroxidation-driven cell death, in tumor cells has emerged as a promising therapeutic target for cancer treatment. Preclinical mouse cancer models have demonstrated that anticancer immunity, mediated by dendritic cells and cytotoxic CD8+ T cells, is essential for effective tumor eradication by ferroptosis-inducing strategies. However, ferroptotic cells limit this response resulting in immune escape and tumor growth, through mechanisms that remain unclear.

We uncover that ferroptotic cancer cells activate a molecular program resulting in aberrant production of the immune-regulatory lipid prostaglandin E2 (PGE2), which limits the stimulation of anti-cancer CD8+ T cell responses by cDC1s, thereby promoting cancer immune escape. Aberrant PGE2 production is selectively triggered by ferroptosis and not induced by other regulated cell death pathways, such as apoptosis. Mechanistically, induction of p38 MAPK signalling through Ca2+ influx drives PGE2 production in ferroptotic cancer cells. This signalling axis is uncoupled from cancer cell death and can be targeted to selectively interfere with immune-inhibitory PGE2 production while preserving ferroptotic cancer cell elimination. In the context of cancer cell ferroptosis, ablation of PGE2 production, as well as disrupting PGE2 signalling in cDC1s, restores cDC1-mediated orchestration of anticancer CD8+ T cell responses and leads to effective tumor elimination. Together, our findings identify a key mechanism that limits cDC-mediated antitumor immunity and prevents tumor elimination upon ferroptosis induction in cancer cells, which could be exploited for cancer therapy.