Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 3, Pages 1109-1114Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI123791
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Funding
- Center for Cancer Research, NCI
- NATIONAL CANCER INSTITUTE [ZICBC011569] Funding Source: NIH RePORTER
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The TP53 gene, encoding the critical p53 tumor suppressor, is the most commonly mutated gene in cancer. Intratumoral T cell responses to mutations occurring frequently at certain TP53 positions, termed hot spots, have not been systematically studied. The 8 most commonly mutated positions in TP53 were found in 33 (24%) of 140 common epithelial tumors analyzed. A TP53-specific screening assay was developed to evaluate T cell responses to these p53 neoepitopes presented though intracellular (tandem minigene) and extracellular (pulsed peptide) pathways on autologous antigen-presenting cells expressing all human leukocyte antigen (HLA) class I and II molecules. Tumor-infiltrating lymphocytes (TILs) from 11 patients recognized autologous p53 neoantigens, which accounted for 8% and 39% of all patients sequenced (n = 140) and screened (n = 28), respectively. These responses were restricted by a variety of HLA restriction elements, including common class I (A*02:01) and class II (DPB1*02:01 and DRB1*13:01) alleles. T cell receptors (TCRs) were identified from TP53 mutation-reactive helper (CD4) and cytotoxic (CD8) T cells, and TIL and TCR gene-engineered T cells recognized tumor cell lines endogenously expressing HLA and mutant TP53. Thus, the most commonly mutated gene in cancer, TP53, appears to be immunogenic and represents an attractive candidate for evaluating targeted immune cancer therapies.
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