TY - JOUR
T1 - T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells
AU - Pont, Margot J.
AU - Oostvogels, Rimke
AU - van Bergen, Cornelis A. M.
AU - van der Meijden, EdithD.
AU - Honders, Maria W.
AU - Bliss, Sophie
AU - Jongsma, Marlieke L. M.
AU - Lokhorst, Henk M.
AU - Falkenburg, J. H. Frederik
AU - Mutis, Tuna
AU - Griffioen, Marieke
AU - Spaapen, Robbert M.
N1 - Funding Information:
T. Mutis reports receiving commercial research funding from Genmab, Takeda, Janssen Pharmaceuticals, Onkimmune, Aduro, and Novartis. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors would like to thank Michel Kester for the production of tetramers and Dr. Marieke von Lindern and Nurcan Yagci for expertise and technical assistance on the isolation of nuclear and cytoplasmic RNA. This work was supported by a NWO-VENI personal grant (016.131.047, to R.M. Spaapen) and by the Dutch Cancer Society (UL 2010-4748, to M. Griffioen).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/5
Y1 - 2019/5
N2 - MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a truncated protein. The antigenic peptide is derived from the gene TTK only through an alternative transcript containing a premature termination codon that may target the transcript for nonsense-mediated decay (NMD). This antigen is recognized by HLA-A02:01–restricted CD8
þ T cells derived from an allotransplanted leukemia patient. Functional analyses showed that these T cells failed to recognize several HLA-matched primary leukemic cells that expressed the alternative TTK transcript. Conventional antigen processing and presentation were not affected, suggesting that leukemic cells modify the generation of antigens processed from aberrant proteins. This natural TTK epitope provides insights in the source of transcripts producing antigenic epitopes in healthy and leukemic cells. Our data underscore potential pitfalls of targeting NMD-derived or other unconventionally generated epitopes as immunotherapeutic approach.
AB - MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a truncated protein. The antigenic peptide is derived from the gene TTK only through an alternative transcript containing a premature termination codon that may target the transcript for nonsense-mediated decay (NMD). This antigen is recognized by HLA-A02:01–restricted CD8
þ T cells derived from an allotransplanted leukemia patient. Functional analyses showed that these T cells failed to recognize several HLA-matched primary leukemic cells that expressed the alternative TTK transcript. Conventional antigen processing and presentation were not affected, suggesting that leukemic cells modify the generation of antigens processed from aberrant proteins. This natural TTK epitope provides insights in the source of transcripts producing antigenic epitopes in healthy and leukemic cells. Our data underscore potential pitfalls of targeting NMD-derived or other unconventionally generated epitopes as immunotherapeutic approach.
UR - http://www.scopus.com/inward/record.url?scp=85065511312&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-18-0137
DO - 10.1158/2326-6066.CIR-18-0137
M3 - Article
SN - 2326-6066
VL - 7
SP - 797
EP - 804
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 5
ER -