Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
Dr. Brian M. Baker
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 CDR3Î² 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.
- Authors: Smita S Chandran, Jiaqi Ma, Martin G Klatt, Friederike Dundar, Chaitanya Bandlamudi, Pedram Razavi, Hannah Y Wen, Britta Weigelt, Paul Zumbo, Si Ning Fu, Lauren B Banks, Fei Yi, Enric Vercher, Inaki Etxeberria, Watchain D Bestman, Arnaud Da Cruz Paula, Ilinca S Aricescu, Alexander Drilon, Doron Betel, David A Scheinberg, Brian M Baker, Christopher A Klebanoff.
- Nat Med. 2022 May;28(5):946-957. doi: 10.1038/s41591-022-01786-3. Epub 2022 Apr 28..