Qdaisat, Wummer, and Stover et al. demonstrated that early type-I interferon responses restored a defective damage response in poorly immunogenic tumors to enable epitope spreading and sensitivity to ICB. ICB response was transferrable to resistant models due to epitope spread against poorly immunogenic tumor antigens in an IFNAR1-dependent manner. Systemic administration of lipid particles loaded with RNA coding for tumor-unspecific antigens enhanced interferon responses, induced epitope spreading, and reprogrammed the TME from myeloid suppressive to pro-inflammatory, favoring effector T cells for sustained immune response in poorly immunogenic models.
Contributed by Shishir Pant
ABSTRACT: The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge. Our findings show that the resistance of tumours to immunotherapy is dictated by the absence of a damage response, which can be restored by boosting early type-I interferon responses to enable epitope spreading and self-amplifying responses in treatment-refractory tumours.
Author Info: (1) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Univer
Author Info: (1) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA. (2) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (3) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (4) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (5) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (6) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (7) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (8) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (10) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (11) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (12) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (13) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (14) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (15) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (16) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (17) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (18) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (19) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (20) Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, USA. (21) Department of Medicine, Division of Hematology and Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (22) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (23) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (24) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (25) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (26) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (27) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (28) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (29) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (30) College of Veterinary Medicine, University of Florida, Gainesville, FL, USA. (31) Department of Pathology, University of Florida, Gainesville, FL, USA. (32) Center of Immunotherapy and Precision Immuno-Oncology/Head and Neck Institute, Cleveland Clinic, Cleveland, OH, USA. (33) Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, USA. (34) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (35) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (36) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (37) Department of Biostatistics, University of Florida, Gainesville, FL, USA. (38) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (39) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (40) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (41) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Elias.Sayour@neurosurgery.ufl.edu. Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. Elias.Sayour@neurosurgery.ufl.edu.
