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Proc Natl Acad Sci U S A. 2019 Nov 4. pii: 201906026. doi: 10.1073/pnas.1906026116. [Epub ahead of print]

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

Linette GP1,2,3,4, Becker-Hapak M5,6,7, Skidmore ZL5,6,7, Baroja ML1,2,3,4, Xu C1,2,3,4, Hundal J5,6,7, Spencer DH5,6,7, Fu W1,2,3,4,8, Cummins C1,2,3,4, Robnett M1,2,3,4, Kaabinejadian S9, Hildebrand WH9, Magrini V10,11, Demeter R5,6,7, Krupnick AS12, Griffith OL5,6,7, Griffith M5,6,7, Mardis ER10,11, Carreno BM13,2,3,4.

Author information

1
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
2
The Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
4
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
5
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110.
6
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
7
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
8
Bioinformatics Core, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
9
Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104.
10
Institute for Genomic Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH 43205.
11
Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH 43205.
12
Department of Surgery, University of Virginia, Charlottesville, VA 22908.
13
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bcarreno@upenn.edu.

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.

KEYWORDS:

CD8+ T cells; cancer vaccine; dendritic cells; melanoma; neoantigen

PMID:
31685621
DOI:
10.1073/pnas.1906026116

Conflict of interest statement

The authors declare no competing interest.

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