Kim and Crosse et al. identified immunogenic and endogenously presented neoantigens derived from shared mis-splicing events in splicing factor SRSF2- or ZRSR2-mutant myeloid leukemias. TCR T cells recognizing the SRSF2 mutant-induced CLK3 neoantigen specifically lysed SRSF2-mutant AML cells, reduced tumor burdens, and extended survival in xenograft models. Neoantigen-specific CD8+ T cells isolated from the peripheral blood of patients with AML were clonally expanded, but with impaired cytotoxicity. After curative allo-transplant, a functional, donor-derived T cell response against the mis-splicing RHOT2 neoantigen was detected.
Contributed by Ute Burkhardt
ABSTRACT: Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8(+) T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing SRSF2 mutant-induced neoantigens arising from mis-splicing events in CLK3 and RHOT2 resulted in specific recognition and cytotoxicity of SRSF2-mutant leukemia. These data identify recurrent RNA mis-splicing events as sources of actionable public neoantigens in myeloid leukemias and provide proof of concept for genetically redirecting T cells to recognize these targets.
Author Info: (1) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (2) Public Health Sciences and Basic Sciences Divisi
Author Info: (1) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (2) Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA. (3) Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. (4) Human Oncology and Pathogenesis Program, MSK, New York, NY, USA. (5) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (6) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (7) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (8) Codify Therapeutics, Cambridge, MA, USA. (9) Department of Medicine, Division of Hematology, Stanford University, Palo Alto, CA, USA. (10) Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA. (11) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (12) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (13) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (14) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (15) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (16) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (17) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (18) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (19) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (20) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (21) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (22) Single-cell Analytics Innovation Laboratory, MSK, New York, NY, USA. (23) Single-cell Analytics Innovation Laboratory, MSK, New York, NY, USA. (24) Single-cell Analytics Innovation Laboratory, MSK, New York, NY, USA. (25) Proteomics Resource Center, Rockefeller University, New York, NY, USA. (26) Single-cell Analytics Innovation Laboratory, MSK, New York, NY, USA. (27) Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Hematopoietic Biology and Malignancy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medical Center, New York, NY, USA. (30) Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medical Center, New York, NY, USA. (31) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. (32) Human Oncology and Pathogenesis Program, MSK, New York, NY, USA. (33) Computational Oncology, Department of Epidemiology and Biostatistics, MSK, New York, NY, USA. (34) Human Oncology and Pathogenesis Program, MSK, New York, NY, USA; Parker Institute for Cancer Immunotherapy, New York, NY, USA. Electronic address: klebanoc@mskcc.org. (35) Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: rbradley@fredhutch.org. (36) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSK), New York, NY, USA. Electronic address: abdelwao@mskcc.org.
