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Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2019
- Publisher :
- Proceedings of the National Academy of Sciences, 2019.
-
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.
- Subjects :
- Lung Neoplasms
Receptors, Antigen, T-Cell, alpha-beta
T cell
T-Cell Antigen Receptor Specificity
Human leukocyte antigen
CD8-Positive T-Lymphocytes
Biology
Cancer Vaccines
Polymorphism, Single Nucleotide
Epitope
Lymphocytes, Tumor-Infiltrating
Antigens, Neoplasm
HLA Antigens
T-Lymphocyte Subsets
medicine
Humans
Cytotoxic T cell
Retroperitoneal Neoplasms
Melanoma
Multidisciplinary
integumentary system
Vaccination
T-cell receptor
DNA, Neoplasm
Dendritic Cells
Sequence Analysis, DNA
Dendritic cell
Clone Cells
medicine.anatomical_structure
Amino Acid Substitution
PNAS Plus
Monoclonal
Cancer research
Tumor Escape
CD8
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....be4fe3d14bce2be3ea8df24b79023bd4