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

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

Publication date: Nov 04, 2019

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.

Linette, G.P., Becker-Hapak, M., Skidmore, Z.L., Baroja, M.L., Xu, C., Hundal, J., Spencer, D.H., Fu, W., Cummins, C., Robnett, M., Kaabinejadian, S., Hildebrand, W.H., , Magrini, Demeter, R., Krupnick, A.S., Griffith, O.L., Griffith, M., Mardis, E.R., and Carreno, B.M. Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens. 24706. 2019 Proc Natl Acad Sci U S A.

Concepts Keywords
Amino Acid Solid tumors
Blood Metastases melanoma
CD8 Oligo clonal melanoma
CDR3 Dilution tumor
Clonal Dendritic melanoma
Clonotype Vaccination
Epitopes Medical specialties
Heterogeneity Medicine
HLA Lymphatic system
Immunity Immune system
ITH Immunology
Lymphocytes Oncology
Melanoma Lymphocytes
Metastases Tumor-infiltrating lymphocytes
Monoclonal Antigen
Neoantigen Cytotoxic T cell
Nucleotide CD8
Oligo Melanoma
Peptides
Receptor
Sci
Sequencing
Throughput
Tumor
Vaccination

Semantics

Type Source Name
disease MESH melanoma
disease DOID melanoma
pathway BSID Melanoma
gene UNIPROT IMPACT
disease MESH tumors
disease MESH development
disease DOID cancer
disease MESH metastases
drug DRUGBANK BK-MDA
gene UNIPROT CCL22
gene UNIPROT ADAM11

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