Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity
(1) Bell HN (2) Nair K (3) Tison K (4) Liao P (5) Lei H (6) El-Derany MO (7) Yisimayi A (8) Zhang H (9) Rebernick R (10) Wang W (11) Adachi Y (12) Castillo C (13) Das NK (14) An J (15) Sutton VR (16) Lin X (17) Lin H (18) Wang X (19) Li Y (20) Vatan L (21) Aboud A (22) Wei S (23) Gijon M (24) Goodwin S (25) Shah YM (26) Kryczek I (27) Trapani JA (28) Barroso M (29) Lieberman J (30) Zou W
Bell et al. discovered a previously unrecognized, granzyme-independent function of perforin (Prf1) in CTLs and NK cells that showed that Prf1 can directly kill tumor cells via ferroptosis. Mechanistically, Prf1 induced transferrin receptor (CD71) endocytosis, leading to increased cellular iron uptake. Via endosomal–mitochondrial contacts, this subsequently elevated mitochondrial iron and lipid peroxidation, and tumor cell ferroptosis. In murine studies, dietary iron supplementation potentiated antitumor immunity in a Prf1-dependent manner, while in patients with cancer, higher Prf1 expression correlated with longer survival and improved responses to ICB.
Contributed by Katherine Turner
(1) Bell HN (2) Nair K (3) Tison K (4) Liao P (5) Lei H (6) El-Derany MO (7) Yisimayi A (8) Zhang H (9) Rebernick R (10) Wang W (11) Adachi Y (12) Castillo C (13) Das NK (14) An J (15) Sutton VR (16) Lin X (17) Lin H (18) Wang X (19) Li Y (20) Vatan L (21) Aboud A (22) Wei S (23) Gijon M (24) Goodwin S (25) Shah YM (26) Kryczek I (27) Trapani JA (28) Barroso M (29) Lieberman J (30) Zou W
Bell et al. discovered a previously unrecognized, granzyme-independent function of perforin (Prf1) in CTLs and NK cells that showed that Prf1 can directly kill tumor cells via ferroptosis. Mechanistically, Prf1 induced transferrin receptor (CD71) endocytosis, leading to increased cellular iron uptake. Via endosomal–mitochondrial contacts, this subsequently elevated mitochondrial iron and lipid peroxidation, and tumor cell ferroptosis. In murine studies, dietary iron supplementation potentiated antitumor immunity in a Prf1-dependent manner, while in patients with cancer, higher Prf1 expression correlated with longer survival and improved responses to ICB.
Contributed by Katherine Turner
ABSTRACT: Cytotoxic CD8(+) T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
Author Info:
(1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel
Cancer Center, Ann Arbor, MI, USA. (2) Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA. (3) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. (4) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (5) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. (6) Department of Molecular & Physiology, University of Michigan, Ann Arbor, MI, USA. (7) Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. (8) Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. (9) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. (10) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (11) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (12) Department of Molecular & Physiology, University of Michigan, Ann Arbor, MI, USA. (13) Department of Molecular & Physiology, University of Michigan, Ann Arbor, MI, USA. (14) Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (16) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (17) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (18) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. (19) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. (20) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. (21) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. (22) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. (23) Cayman Chemical, Ann Arbor, MI, USA. (24) Cayman Chemical, Ann Arbor, MI, USA. (25) Department of Molecular & Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. (26) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address: ilonak@umich.edu. (27) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (28) Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA. Electronic address: barrosm@amc.edu. (29) Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu. (30) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address: wzou@umich.edu.
