T cell receptor profiling of blood for early detection of lung cancer 2685

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Abstract Description Lung cancer is the leading cause of cancer-related deaths – thus new biomarkers for early detection are needed. Given the high mutational burden of lung cancer and its association with a strong anti-tumor immune response, we investigated the use of blood TCR profiling for early detection of lung cancer. We sequenced PBMCs from 633 individuals, divided into a case-control (n = 511) and a lung cancer screening cohort (n = 122), identifying over 12.6 million unique TCRβ clonotypes. We devised a Tumor Immune Lymphocyte Score (TILS) using either TCR specificity groups (TILS-A, 125 groups) or ‘public’ TCRβ-Vβ clonotypes (TILS-B, 49 clonotypes) capable of detecting lung cancer. TILS classifiers were strongly associated with lung cancer in both cohorts, and TILS-A and TILS-B TCRs were enriched in tumor compared to uninvolved adjacent lung tissue in an external cohort. When integrated with other T cell-associated variables and clinical variables of risk, TILS classifiers markedly improved cancer prediction accuracy (AUC = 0.925 vs 0.904). Notably, TILS-A significantly improved cancer risk prediction in the screening cohort (NRI = 0.232), particularly for individuals with otherwise indeterminate risk. Subgroup analysis showed TILS-A was associated with both early and late-stage disease. Moreover, TILS-A prediction accuracy was improved when adjusted for HLA status. These findings highlight blood TCR profiling as a promising tool for early lung cancer detection and diagnosis. Topic Categories Translational and Interventional Immunology (TI)

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