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Immune repertoire deep sequencing allows comprehensive characterization of antigen receptor-encoding genes in a lymphocyte population. We hypothesized that this method could enable a novel approach to diagnose disease by identifying antigen receptor sequence patterns associated with clinical phenotypes. In this study, we developed statistical classifiers of T-cell receptor (TCR) repertoires that distinguish tumor tissue from patient-matched healthy tissue of the same organ. The basis of both classifiers was a biophysicochemical motif in the complementarity determining region 3 (CDR3) of TCRβ chains. To develop each classifier, we extracted 4-mers from every TCRβ CDR3 and represented each 4-mer using biophysicochemical features of its amino acid sequence combined with quantification of 4-mer (or receptor) abundance. This representation was scored using a logistic regression model. Unlike typical logistic regression, the classifier is fitted and validated under the requirement that at least 1 positively labeled 4-mer appears in every tumor repertoire and no positively labeled 4-mers appear in healthy tissue repertoires. We applied our method to publicly available data in which tumor and adjacent healthy tissue were collected from each patient. Using a patient-holdout cross-validation, our method achieved classification accuracy of 93% and 94% for colorectal and breast cancer, respectively. The parameter values for each classifier revealed distinct biophysicochemical properties for tumor-associated 4-mers within each cancer type. We propose that such motifs might be used to develop novel immune-based cancer screening assays. SIGNIFICANCE: This study presents a novel computational approach to identify T-cell repertoire differences between normal and tumor tissue. See related commentary by Zoete and Coukos, p. 1299 ., (©2019 American Association for Cancer Research.)