Chandran et al. isolated 4 distinct TCRs from 4 healthy donors following in vitro stimulation of naive T cells with autologous DCs expressing 4 mutations in PIK3CA (a driver oncogene). Each TCR recognized H1047L PIK3CA, a mutation harbored in 77.9% of 131 tumors surveyed. Recognition was restricted by HLA - A*03:01, an allele expressed in 20-28% of individuals. Signal transduction through these TCRs mediated inflammatory and lytic responses. H1047L PIK3CA-specific T cells were detected in 4 (29%) of the 14 patients analyzed. Cells expressing TCR that recognized H1047L PIK3CA inhibited tumor growth in NSG mice.
Contributed by Margot O’Toole
ABSTRACT: Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.
Author Info: (1) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org. Center for Cell Engineer
Author Info: (1) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chandrs1@mskcc.org. Parker Institute for Cancer Immunotherapy, New York, NY, USA. chandrs1@mskcc.org. (2) Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, USA. Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA. (3) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA. (5) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA. Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA. (10) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. (20) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, USA. Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA. (22) Human Oncology and Pathogenesis Program (HOPP), Immuno-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org. Center for Cell Engineering, 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. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA. klebanoc@mskcc.org. Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org. Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. klebanoc@mskcc.org.
