Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens

Gerald P. Linette, Michelle Becker-Hapak, Zachary L. Skidmore, Miren Lorea Baroja, Chong Xu, Jasreet Hundal, David H. Spencer, Weixuan Fu, Casey Cummins, Maya Robnett, Saghar Kaabinejadian, William H. Hildebrand, Vincent Magrini, Ryan Demeter, Alexander S. Krupnick, Obi L. Griffith, Malachi Griffith, Elaine R. Mardis, Beatriz M. Carreno

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαβ heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.

Original languageEnglish
Pages (from-to)23662-23670
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number47
DOIs
StatePublished - Nov 19 2019

Keywords

  • CD8+ T cells
  • Cancer vaccine
  • Dendritic cells
  • Melanoma
  • Neoantigen

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