A novel source of tumor antigens are cancer-specific splicing events known as neojunctions (NJs). Kwok et al. investigated the clonality of NJs across different cancer types and found that NJs are expressed tumor-wide and persist spatially and temporally. The NJs could generate HLA-presented neopeptides that could be recognized by TCRs and induce cytotoxic T cell responses.
ABSTRACT: T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system's recognition of cancer-specific antigens(1). However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity(2-4). Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cells under physiologic conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8(+) T_cells. Moreover, our study highlights a role for dysregulated splicing factor expression in specific cancer types, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoural heterogeneity.
Author Info: (1) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (2) Department of Neurological Surgery, University of California, San Franc
Author Info: (1) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (2) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (3) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Parker Institute for Cancer Immunotherapy, New York, NY, USA. (4) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (5) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (6) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (7) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (8) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (9) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Department of Neurosurgery, University Hospital Muenster, Muenster, Germany. (11) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA. (12) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (13) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (14) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (15) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (16) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA. (17) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (18) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (19) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (20) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (21) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (22) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (23) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (24) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (25) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (26) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. (27) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. (28) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA. (29) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org. Parker Institute for Cancer Immunotherapy, New York, NY, USA. klebanoc@mskcc.org. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org. (30) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. joseph.costello@ucsf.edu. (31) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. hideho.okada@ucsf.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. hideho.okada@ucsf.edu.
